Process for the manufacture of enol derivatives

ABSTRACT

7β-Amino-3-cephem-3-cl-4-carboxylic acid compounds of the formula ##STR1## wherein R 1   a  represents hydrogen or an amino protective group R 1   A  and R 1   b  represents hydrogen or an acyl group Ac, or R 1   a  and R 1   b  together represent a bivalent amino protective group, R 2  represents hydroxyl or a radical R 2   A  which together with the carbonyl grouping --C(═O)-- forms a protected carboxyl group and R 3  represents hydrogen, lower alkyl or a hydroxyl protective group, and 1-oxides of 3-cephem compounds of the formula IA, and the corresponding 2-cephem compounds are prepared in that a compound of the formula ##STR2## wherein R 1   a , R 1   b  and R 2   A  have the meanings mentioned under formula IA, R 3   o  represents lower alkyl or a hydroxyl protective group and Y represents a group which is removed, is treated with a base; also comprised are intermediate products.

This is a divisional of application Ser. No. 962,425 filed on Nov. 20,1978 No. 4,255,328; which is a division of application Ser. No. 746,927,filed on Dec. 2, 1976 now U.S. Pat. No. 4,147,864; which is acontinuation of Ser. No. 551,483, filed on Feb. 20, 1975, now abandoned.

The subject of the present invention is a process for the manufacture ofenol derivatives, especially 7β-amino-3-cephem-3-ol-4-carboxylic acidcompounds of the formula ##STR3## wherein R₁ ^(a) represents hydrogen oran amino protective group R₁ ^(A) and R₁ ^(b) represents hydrogen or anacyl group Ac, or R₁ ^(a) and R₁ ^(b) together represent a bivalentamino protective group, R₂ represents hydroxyl or a radical R₂ ^(A)which together with the carbonyl grouping --C(═O)-- forms a protectedcarboxyl group and R₃ represents hydrogen, lower alkyl or a hydroxylprotective group, and 1-oxides of 3-cephem compounds of the formula IAand the corresponding 2-cephem compounds of the formula ##STR4## whereinR₁ ^(a), R₁ ^(b), R₂ and R₃ have the abovementioned meanings, or saltsof such compounds with salt-forming groups. The enol derivatives of thepresent invention are ethers of 3-cephem-3-ol or 2-cephem-3-olcompounds.

In 2-cephem compounds of the formula IB having the double bond in the2,3-position, the optionally protected carboxyl group of the formula--C(═O)--R₂ preferably has the α-configuration.

An amino protective group R₁ ^(A) is a group which can be replaced byhydrogen, above all an acyl group Ac, also a triarylmethyl group,especially the trityl group, as well as an organic silyl group, or anorganic stannyl group. A group Ac, which can also represent a radical R₁^(b), above all represents the acyl radical of an organic carboxylicacid, preferably with up to 18 carbon atoms, especially the acyl radicalof an optionally substituted aliphatic, cycloaliphatic,cycloaliphatic-aliphatic, aromatic, araliphatic, heterocyclic orheterocyclic-aliphatic carboxylic acid (including formic acid) and theacyl radical of a carbonic acid half-derivative.

A bivalent amino protective group formed by the radicals R₁ ^(a) and R₁^(b) together is, in particular, the bivalent acyl radical of an organicdicarboxylic acid, preferably with up to 18 carbon atoms, above all thediacyl radical of an aliphatic or aromatic dicarboxylic acid, and alsothe acyl radical of an α-aminoacetic acid which is preferablysubstituted in the α-position and contains, for example, an aromatic orheterocyclic radical, and wherein the amino group is bonded to thenitrogen atom via a methylene radical which is preferably substitutedand, for example, contains two lower alkyl groups, such as methylgroups. The radicals R₁ ^(a) and R₁ ^(b) can together also represent anorganic ylidene radical, such an an aliphatic, cycloaliphatic,cycloaliphatic-aliphatic or araliphatic ylidene radical, preferably withup to 18 carbon atoms.

A protected carboxyl group of the formula --C(═O)--R₂ ^(A) is above allan esterified carboxyl group but can also be an anhydride group, usuallya mixed anhydride group, or an optionally substituted carbamoyl orhydrazinocarbonyl group.

The group R₂ ^(A) can therefore be a hydroxyl group etherified by anorganic radical, wherein the organic radical preferably contains up to18 carbon atoms, which together with the --C(═O)-- grouping forms anesterified carboxyl group. Examples of such organic radicals arealiphatic, cycloaliphatic, cycloaliphatic-aliphatic, aromatic oraraliphatic radicals, especially optionally substituted hydrocarbonradicals of this nature, as well as heterocyclic orheterocyclicaliphatic radicals.

The group R₂ ^(A) can also represent an organic silyloxy radical as wellas a hydroxyl group etherified by an organometallic radical, such as anappropriate organic stannyloxy group, especially a silyloxy orstannyloxy group which is substituted by 1 to 3 optionally substitutedhydrocarbon radicals, preferably with up to 18 carbon atoms, such asaliphatic hydrocarbon radicals, and optionally by halogen, such aschlorine.

A radical R₂ ^(A) which forms, with a --C(═O)-- grouping, an anhydridegroup, above all a mixed anhydride group, is for example halogen, suchas chlorine or an acyloxy radical, wherein acyl represents thecorresponding radical of an organic carboxylic acid, preferably with upto 18 carbon atoms, such as of an aliphatic, cycloaliphatic,cycloaliphatic-aliphatic, aromatic or araliphatic carboxylic acid or ofa carbonic acid half-derivative, such as of a carbonic acid half-ester.

A radical R₂ ^(A) which forms a carbamoyl group with a --C(═O)--grouping is an optionally substituted amino group wherein substituentsrepresent optionally substituted monovalent or bivalent hydrocarbonradicals, preferably with up to 18 carbon atoms, such as optionallysubstituted monovalent or bivalent aliphatic, cycloaliphatic,cycloaliphatic-aliphatic, aromatic or araliphatic hydrocarbon radicalswith up to 18 carbon atoms, also appropriate heterocyclic orheterocyclic-aliphatic radicals with up to 18 carbon atoms and/orfunctional groups, such as optionally functionally modified, butespecially free, hydroxyl and also etherified or esterified hydroxyl,wherein the etherifying or esterifying radicals have, for example, theabovementioned meanings and preferably contain up to 18 carbon atoms, aswell as acyl radicals, above all of organic carboxylic acids and ofcarbonic acid half-derivatives, preferably with up to 18 carbon atoms.

In a substituted hydrazinocarbonyl group of the formula --C(═O)--R₂^(A), one or both nitrogen atoms can be substituted, possiblesubstituents being above all optionally substituted monovalent orbivalent hydrocarbon radicals, preferably with up to 18 carbon atoms,such as optionally substituted, monovalent or bivalent aliphatic,cycloaliphatic, cycloaliphatic-aliphatic, aromatic or araliphatichydrocarbon radicals with up to 18 carbon atoms and also appropriateheterocyclic or heterocyclic-aliphatic radicals with up to 18 carbonatoms and/or functional groups, such as acyl radicals, above all oforganic carboxylic acids or of carbonic acid half-derivatives,preferably with up to 18 carbon atoms.

A lower alkyl group R₃ has up to 7, preferably up to 4, carbon atoms andis, in particular, methyl.

A hydroxyl protective group R₃ is, for example, an easily removable2-oxa-aliphatic or 2-thia-aliphatic or 2-oxa-cycloaliphatic or2-thia-cycloaliphatic hydrocarbon radical, an easily removablesubstituted silyl or stannyl group, or an also easily removable,optionally substituted, α-phenyl-lower alkyl group, such as anoptionally substituted benzyl or diphenylmethyl group.

The general concepts used in the preceding and following descriptionhave, for example, the following meanings:

An aliphatic radical, including the aliphatic radical of an appropriateorganic carboxylic acid, as well as an appropriate ylidene radical, isan optionally substituted monovalent or divalent aliphatic hydrocarbonradical, especially lower alkyl, as well as lower alkenyl or loweralkinyl, and also lower alkylidene which can contain, for example, up to7, preferably up to 4, carbon atoms. Such radicals can optionally bemonosubstituted, disubstituted or polysubstituted by functional groups,for example by free, etherified or esterified hydroxyl or mercaptogroups, such as lower alkoxy, lower alkenyloxy, lower alkylenedioxy,optionally substituted phenyloxy or phenyl-lower alkoxy, lower alkylthioor optionally substituted phenylthio, phenyl-lower alkylthio,heterocyclylthio or heterocyclyl-lower alkylthio, optionally substitutedlower alkoxycarbonyloxy or lower alkanoyloxy, or halogen, also by oxo,nitro, optionally substituted amino, for example lower alkylamino,di-lower alkylamino, lower alkyleneamino, oxa-lower alkyleneamino oraza-lower alkyleneamino, as well as acylamino, such as loweralkanoylamino, lower alkoxycarbonylamino, halogeno-loweralkoxycarbonylamino, optionally substituted phenyl-loweralkoxycarbonylamino, optionally substituted carbamoylamino,ureidocarbonylamino or guanidinocarbonylamino and also sulphoamino whichis optionally present in the form of a salt, such as in the form of analkali metal salt, azido, acyl, such as lower alkanoyl or benzoyl,optionally functionally modified carboxyl, such as carboxyl present inthe form of a salt, esterified carboxyl, such as lower alkoxycarbonyl,optionally substituted carbamoyl, such as N-lower alkylcarbamoyl orN,N-di-lower alkylcarbamoyl and also optionally substitutedureidocarbonyl or guanidinocarbonyl, or nitrile, optionally functionallymodified sulpho, such as sulphamoyl or sulpho present in the form of asalt, or optionally O-monosubstituted or O,O-disubstituted phosphono,wherein substituents represent, for example, optionally substitutedlower alkyl, phenyl or phenyl-lower alkyl, it also being possible forO-unsubstituted or O-monosubstituted phosphono to be in the form of asalt, such as in the form of an alkali metal salt.

A bivalent aliphatic radical, including the appropriate radical of abivalent aliphatic carboxylic acid, is, for example, lower alkylene orlower alkylene, which can optionally be monosubstituted, disubstitutedor polysubstituted, for example like an aliphatic radical indicatedabove, and/or be interrupted by hetero-atoms, such as oxygen, nitrogenor sulphur.

A cycloaliphatic or cycloaliphatic-aliphatic radical, including thecycloaliphatic or cycloaliphatic-aliphatic radical in an appropriateorganic carboxylic acid or an appropriate cycloaliphatic orcycloaliphatic-aliphatic ylidene radical, is an optionally substituted,monovalent or bivalent, cycloaliphatic or cycloaliphatic-aliphatichydrocarbon radical, for example monocyclic, bicyclic or polycycliccycloalkyl or cycloalkenyl, and also cycloalkylidene, or cycloalkyl- orcycloalkenyl-lower alkyl or -lower alkenyl, as well as cycloalkyl-loweralkylidene or cycloalkenyl-lower alkylidene, wherein cycloalkyl andcycloalkylidene contains, for example, up to 12, such as 3-8, preferably3-6, ring carbon atoms, whilst cycloalkenyl contains, for example, up to12, such as 3-8, for example 5-8, preferably 5 or 6, ring carbon atomsand 1 to 2 double bonds, and the aliphatic part of acycloaliphatic-aliphatic radical can contain, for example, up to 7,preferably up to 4, carbon atoms. The above cycloaliphatic orcycloaliphatic-aliphatic radicals can, if desired, be monosubstituted,disubstituted or polysubstituted, for example by optionally substitutedaliphatic hydrocarbon radicals, such as by the abovementioned optionallysubstituted lower alkyl groups or, for example, like the abovementionedaliphatic hydrocarbon radicals, by functional groups.

An aromatic radical, including the aromatic radical of an appropriatecarboxylic acid, is an optionally substituted aromatic hydrocarbonradical, for example a monocyclic, bicyclic or polycyclic aromatichydrocarbon radical, especially phenyl, as well as biphenylyl ornaphthyl, which can optionally be monosubstituted, disubstituted orpolysubstituted, for example like the abovementioned aliphatic andcycloaliphatic hydrocarbon radicals.

A bivalent aromatic radical, for example of an aromatic carboxylic acid,is above all 1,2-arylene, especially 1,2-phenylene, which can optionallybe monosubstituted, disubstituted or polysubstituted, for example likethe abovementioned aliphatic and cycloaliphatic hydrocarbon radicals.

An araliphatic radical, including the araliphatic radical in anappropriate carboxylic acid, and also an araliphatic ylidene radical,is, for example, an optionally substituted araliphatic hydrocarbonradical, such as an aliphatic hydrocarbon radical which is optionallysubstituted and possesses, for example, up to three optionallysubstituted monocyclic, bicyclic or polycyclic aromatic hydrocarbonradicals, and above all represents phenyl-lower alkyl or phenyl-loweralkenyl as well as phenyl-lower alkinyl and also phenyl-loweralkylidene, it being possible for such radicals to contain, for example,1-3 phenyl groups and to be optionally monosubstituted, disubstituted orpolysubstituted in the aromatic and/or aliphatic part, for example likethe above-mentioned aliphatic and cycloaliphatic radicals.

Heterocyclic groups, including those in heterocyclic-aliphatic radicals,including heterocyclic or heterocyclic-aliphatic groups in appropriatecarboxylic acids, are especially monocyclic, as well as bicyclic orpolycyclic, azacyclic, thiacyclic, oxacyclic, thiazacyclic,thiadiazacyclic, oxazacyclic, diazacyclic, triazacyclic or tetrazacyclicradicals of aromatic character, and also appropriate partially or whollysaturated heterocyclic radicals of this nature and such radicals canoptionally be monosubstituted, disubstituted or polysubstituted, forexample like the abovementioned cycloaliphatic radicals. The aliphaticpart in heterocyclic-aliphatic radicals has, for example, the meaningindicated for the corresponding cycloaliphatic-aliphatic or araliphaticradicals.

The acyl radical of a carbonic acid half-derivative is preferably theacyl radical of an appropriate half-ester, wherein the organic radicalof the ester group represents an optionally substituted aliphatic,cycloaliphatic, aromatic or araliphatic hydrocarbon radical or aheterocyclic-aliphatic radical, above all the acyl radical of a loweralkyl half-ester of carbonic acid which is optionally substituted, forexample in the α- or β-position, as well as of a lower alkenyl,cycloalkyl, phenyl or phenyl-lower alkyl half-ester of carbonic acidwhich is optionally substituted in the organic radical. Acyl radicals ofa carbonic acid half-ester are furthermore appropriate radicals of loweralkyl half-esters of carbonic acid, in which the lower alkyl partcontains a heterocyclic group, for example one of the abovementionedheterocyclic groups of aromatic character, and both the lower alkylradical and the heterocyclic group can optionally be substituted. Theacyl radical of a carbonic acid half-derivative can also be anoptionally N-substituted carbamoyl group, such as an optionallyhalogenated N-lower alkylcarbamoyl group.

An etherified hydroxyl group is above all optionally substituted loweralkoxy, wherein substituents above all represent free or functionallymodified, such as etherified or esterified, hydroxyl groups, especiallylower alkoxy or halogen, also lower alkenyloxy, cycloalkyloxy oroptionally substituted phenyloxy, as well as heterocyclyloxy orheterocyclyl-lower alkoxy especially also optionally substitutedphenyl-lower alkoxy.

An optionally substituted amino group is, for example, amino, loweralkylamino, di-lower alkylamino, lower alkyleneamino, oxa-loweralkyleneamino, thia-lower alkyleneamino, aza-lower alkyleneamino,hydroxyamino, lower alkoxyamino, lower alkanoyloxyamino, loweralkoxycarbonylamino or lower alkanoylamino.

An optionally substituted hydrazino group is, for example, hydrazino,2-lower alkylhydrazino, 2,2-di-lower alkylhydrazino, 2-loweralkoxycarbonylhydrazino or 2-lower alkanoylhydrazino.

Lower alkyl is, for example, methyl, ethyl, n-propyl, isopropyl,n-butyl, isobutyl, sec.-butyl or tert.-butyl, as well as n-pentyl,isopentyl, n-hexyl, isohexyl or n-heptyl, whilst lower alkenyl can, forexample, be vinyl, allyl, isopropenyl, 2 or 3-methallyl or 3-butenyl,lower alkinyl can, for example, be propargyl or 2-butinyl and loweralkylidene can, for example, be isopropylidene or isobutylidene.

Lower alkylene is, for example, 1,2-ethylene, 1,2-or 1,3-propylene,1,4-butylene, 1,5-pentylene or 1,6-hexylene, whilst lower alkenylene is,for example, 1,2-ethenylene or 2-buten-1,4-ylene. Lower alkyleneinterrupted by hetero-atoms is, for example, oxa-lower alkylene, such as3-oxa-1,5-pentylene, thia-lower alkylene, such as 3-thia-1,5-pentylene,or aza-lower alkylene, such as 3-lower alkyl-3-aza-1,5-pentylene, forexample 3-methyl-3-aza-1,5-pentylene.

Cycloalkyl is, for example, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl or cycloheptyl as well as adamantyl, cycloalkenyl is, forexample, cyclopropenyl, 1-, 2- or 3-cyclopentenyl, 1-, 2- or3-cyclohexenyl, 3-cycloheptenyl or 1,4-cyclohexadienyl andcycloalkylidene is, for example, cyclopentylidene or cyclohexylidene.Cycloalkyl-lower alkyl or -lower alkenyl is, for example, cyclopropyl-,cyclopentyl-, cyclohexyl- or cycloheptyl-methyl, -1,1- or -1,2-ethyl,-1,1-, -1,2- or -1,3-propyl, -vinyl or -allyl, whilst cycloalkenyl-loweralkyl or -lower alkenyl represents, for example, 1-, 2- or3-cyclopentenyl-, 1-, 2- or 3-cyclohexenyl- or 1-, 2- or3-cycloheptenyl-methyl, -1,1- or -1,2-ethyl, -1,1-, -1,2- or-1,3-propyl, -vinyl or -allyl. Cycloalkyl-lower alkylidene is, forexample, 3-cyclohexenylmethylene.

Naphthyl is 1- or 2-naphthyl, whilst biphenylyl represents, for example,4-biphenylyl.

Phenyl-lower alkyl or phenyl-lower alkenyl is, for example, benzyl, 1-or 2-phenylethyl, 1-, 2- or 3-phenylpropyl, diphenylmethyl, trityl,styryl or cinnamyl, naphthyl-lower alkyl is, for example, 1- or2-naphthylmethyl and phenyl-lower alkylidene is, for example,benzylidene.

Heterocyclic radicals are above all optionally substituted heterocyclicradicals of aromatic character, for example appropriate monocyclic,monoazacyclic, monothiacyclic or monooxacyclic radicals, such as pyrryl,for example 2-pyrryl or 3-pyrryl, pyridyl, for example 2-, 3- or4-pyridyl and also pyridinium, thienyl, for example 2- or 3-thienyl, orfuryl, for example 2-furyl, bicyclic monoazacyclic, monooxacyclic ormonothiacyclic radicals, such as indolyl, for example 2- or 3-indolyl,quinolyl, for example 2- or 4-quinolyl, isoquinolinyl, for example1-isoquinolinyl, benzofuranyl, for example 2- or 3-benzofuranyl, orbenzothienyl, for example 2- or 3-benzothienyl, monocyclic diazacyclic,triazacyclic, tetrazacyclic, oxazacyclic, thiazacyclic orthiadiazacyclic radicals, such as imidazolyl, for example 2-imidazolyl,pyrimidinyl, for example 2- or 4-pyrimidinyl, triazolyl, for example1,2,4-triazol-3-yl, tetrazolyl, for example 1- or 5-tetrazolyl,oxazolyl, for example 2-oxazolyl, isoxazolyl, for example 3- or4-isoxazolyl, thiazolyl, for example 2-thiazolyl, isothiazolyl, forexample 3- or 4-isothiazolyl, or 1,2,4- or 1,3,4-thiadiazolyl, forexample 1,2,4-thiadiazol-3-yl or 1,3,4-thiadiazol-2-yl, or bicyclicdiazacyclic, oxazacyclic or thiazacyclic radicals, such asbenzimidazolyl, for example 2-benzimidazolyl, benzoxazolyl, for example2-benzoxazolyl, or benzthiazolyl, for example 2-benzthiazolyl.Appropriate partially or wholly saturated radicals are, for example,tetrahydrothienyl, such as 2-tetrahydrothienyl, tetrahydrofuryl, such as2-tetrahydrofuryl, or piperidyl, for example 2- or 4-piperidyl.Heterocyclic-aliphatic radicals are lower alkyl or lower alkenylcontaining heterocyclic groups, especially those mentioned above. Theabovementioned heterocyclyl radicals can be substituted, for example byoptionally substituted aliphatic or aromatic hydrocarbon radicals,especially lower alkyl, such as methyl, or phenyl which is optionallysubstituted, for example by halogen such as chlorine, for example phenylor 4-chlorophenyl, or, for example like the aliphatic hydrocarbonradicals, by functional groups.

Lower alkoxy is, for example, methoxy, ethoxy, n-propoxy, isopropoxy,n-butoxy, isobutoxy, sec.-butoxy, tert.-butoxy, n-pentoxy ortert.-pentoxy. These groups can be substituted, for example as inhalogeno-lower alkoxy, especially 2-halogeno-lower alkoxy, for example2,2,2-trichloroethoxy, 2-chloroethoxy, 2-bromoethoxy or 2-iodoethoxy.Lower alkenyloxy is, for example, vinyloxy or allyloxy, loweralkylenedioxy is, for example, methylenedioxy, ethylenedioxy orisopropylidenedioxy, cycloalkoxy is, for example, cyclopentyloxy,cyclohexyloxy or adamantyloxy, phenyl-lower alkoxy is, for example,benzyloxy, 1- or 2-phenylethoxy, diphenylmethoxy or4,4'-dimethoxy-diphenylmethoxy and heterocyclyloxy or heterocyclyl-loweralkoxy is, for example, pyridyl-lower alkoxy, such as 2-pyridylmethoxy,furyl-lower alkoxy, such as furfuryloxy, or thienyl-lower alkoxy, suchas 2-thenyloxy.

Lower alkylthio is, for example, methylthio, ethylthio or n-butylthio,lower alkenylthio is, for example, allylthio, and phenyl-lower alkylthiois, for example, benzylthio, whilst mercapto groups etherified byheterocyclyl radicals or heterocyclyl-aliphatic radicals are especiallypyridylthio, for example 4-pyridylthio, imidazolylthio, thiazolylthio,for example 2-thiazolylthio, 1,2,4- or 1,3,4-thiadiazolylthio, forexample 1,2,4-thiadiazol-3-ylthio or 1,3,4-thiadiazol-2-ylthio, ortetrazolylthio, for example 1-methyl-5-tetrazolylthio.

Esterified hydroxyl groups are above all halogen, for example fluorine,chlorine, bromine or iodine, as well as lower alkoxycarbonyloxy, forexample methoxycarbonyloxy, ethoxycarbonyloxy ortert.-butoxycarbonyloxy, 2-halogenolower alkoxycarbonyloxy, for example2,2,2-trichloroethoxycarbonyloxy, 2-bromoethoxycarbonyloxy or2-iodoethoxycarbonyloxy, or arylcarbonylmethoxycarbonyloxy, for examplephenacyloxycarbonyloxy.

Lower alkoxycarbonyl is, for example, methoxycarbonyl, ethoxycarbonyl,n-propoxycarbonyl, isopropoxycarbonyl, tert.-butoxycarbonyl ortert.-pentoxycarbonyl.

N-lower alkyl- or N,N-di-lower alkyl-carbamoyl is, for example,N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl orN,N-diethylcarbamoyl, whilst N-lower alkylsulphamoyl represents, forexample, N-methylsulphamoyl or N,N-dimethylsulphamoyl.

A carboxyl or sulpho present in the form of an alkali metal salt is, forexample, a carboxyl or sulpho present in the form of a sodium orpotassium salt.

Lower alkylamino or di-lower alkylamino is, for example, methylamino,ethylamino, dimethylamino or diethylamino, lower alkyleneamino is, forexample, pyrrolidino or piperidino, oxa-lower alkyleneamino is, forexample, morpholino, thia-lower alkyleneamino is, for example,thiomorpholino, and aza-lower alkyleneamino is, for example piperazinoor 4-methylpiperazino. Acylamino in particular representscarbamoylamino, lower alkylcarbamoylamino, such as methylcarbamoylamino,ureidocarbonylamino, guanidinocarbonylamino, lower alkoxycarbonylamino,for example methoxycarbonylamino, ethoxycarbonylamino ortert.-butoxycarbonylamino, halogenolower alkoxycarbonylamino, such as2,2,2-trichloroethoxycarbonylamino, phenyl-lower alkoxycarbonylamino,such as 4-methoxybenzyloxycarbonylamino, lower alkanoylamino, such asacetylamino or propionylamino, and also phthalimido, or sulphoaminooptionally present in the form of a salt, such as in the form of analkali metal salt, for example in the form of a sodium salt or ammoniumsalt.

Lower alkanoyl is, for example, formyl, acetyl, propionyl or pivaloyl.

O-lower alkyl-phosphono is, for example O-methyl- or O-ethyl-phosphono,O,O'-di-lower alkyl-phosphono is, for example, O,O-dimethyl-phosphono orO,O'-diethylphosphono, O-phenyl-lower alkyl-phosphono is, for example,O-benzyl-phosphono, and O-lower alkyl-O'-phenyl-lower alkyl-phosphonois, for example, O-benzyl-O'-methyl-phosphono.

Lower alkenyloxycarbonyl is, for example, vinyloxycarbonyl, whilstcycloalkoxycarbonyl and phenyl-lower alkoxycarbonyl represent, forexample, adamantyloxycarbonyl, benzyloxycarbonyl,4-methoxy-benzyloxycarbonyl, diphenylmethoxycarbonyl orα-4-biphenyl-α-methyl-ethoxycarbonyl. Lower alkoxycarbonyl, whereinlower alkyl contains, for example, a monocyclic, monoazacyclic,monooxacyclic or monothiacyclic group, is, for example, furyl-loweralkoxycarbonyl, such as furfuryloxycarbonyl, or thienyl-loweralkoxycarbonyl, such as 2-thenyloxycarbonyl.

2-Lower alkylhydrazino and 2,2-di-lower alkylhydrazino are, for example,2-methylhydrazino or 2,2-dimethylhydrazino, 2-loweralkoxycarbonylhydrazino is, for example, 2-methoxycarbonylhydrazino,2-ethoxycarbonylhydrazino or 2-tert.-butoxycarbonylhydrazino and loweralkanoylhydrazino is, for example, 2-acetylhydrazino.

An acyl group Ac in particular represents an acyl radical of an organiccarboxylic acid, preferably with up to 18 carbon atoms, contained in anaturally occurring or biosynthetically, semi-synthetically ortotal-synthetically obtainable, preferably pharmacologically active,N-acyl derivative of a 6-amino-penam-3-carboxylic acid compound or7-amino-3-cephem-4-carboxylic acid compound, or represents an easilyremovable acyl radical, especially of a carbonic acid half-derivative.

An acyl radical Ac contained in a pharmacologically active N-acylderivative of a 6-amino-penam-3-carboxylic acid compound or7-amino-3-cephem-4-carboxylic acid compound is above all a group of theformula ##STR5## wherein n represents 0 and R^(I) denotes hydrogen or anoptionally substituted cycloaliphatic or aromatic hydrocarbon radical oran optionally substituted heterocyclic radical, preferably of aromaticcharacter, a functionally modified, for example esterified oretherified, hydroxyl or mercapto group or an optionally substitutedamino group, or wherein n represents 1, R^(I) represents hydrogen or anoptionally substituted aliphatic, cycloaliphatic,cycloaliphatic-aliphatic, aromatic or araliphatic hydrocarbon radical oran optionally substituted heterocyclic or heterocyclic-aliphaticradical, wherein the heterocyclic radical preferably possesses aromaticcharacter and/or a quaternary nitrogen atom, an optionally functionallymodified, preferably etherified or esterified, hydroxyl or mercaptogroup, an optionally functionally modified carboxyl group, an acylgroup, an optionally substituted amino group or an azido group and eachof the radicals R^(II) and R^(III) denotes hydrogen, or wherein nrepresents 1, R^(I) denotes an optionally substituted aliphatic,cycloaliphatic, cycloaliphatic-aliphatic, aromatic or araliphatichydrocarbon radical or an optionally substituted heterocyclic orheterocyclic-aliphatic radical, wherein the heterocyclic radicalpreferably has aromatic character, R^(II) denotes an optionallyfunctionally modified, for example esterified or etherified, hydroxyl ormercapto group, such as a halogen atom, an optionally substituted aminogroup, an optionally functionally modified carboxyl or sulpho group, anoptionally O-monosubstituted or O,O'-disubstituted phosphono group or anazido group and R^(III) represents hydrogen, or wherein n represents 1,each of the radicals R^(I) and R^(III) denotes a functionally modified,preferably etherified or esterified, hydroxyl group or an optionallyfunctionally modified carboxyl group, and R^(III) represents hydrogen,or wherein n represents 1, R^(I) denotes hydrogen or an optionallysubstituted aliphatic, cycloaliphatic, cycloaliphatic-aliphatic,aromatic or araliphatic hydrocarbon radical and R^(II) and R^(III)together represent an optionally substituted aliphatic, cycloaliphatic,cycloaliphatic-aliphatic or araliphatic hydrocarbon radical which isboned to the carbon atom by a double bond, or wherein n represents 1 andR^(I) denotes an optionally substituted aliphatic, cycloaliphatic,cycloaliphatic-aliphatic, aromatic or araliphatic hydrocarbon radical oran optionally substituted heterocyclic or heterocyclic-aliphaticradical, wherein heterocyclic radicals preferably possess aromaticcharacter, R^(II) denotes an optionally substituted aliphatic,cycloaliphatic, cycloaliphatic-aliphatic, aromatic or araliphatichydrocarbon radical and R^(III) denotes hydrogen or an optionallysubstituted aliphatic, cycloaliphatic, cycloaliphatic-aliphatic,aromatic or araliphatic hydrocarbon radical.

In the abovementioned acyl groups of the formula A, for example, nrepresents 0 and R^(I) represents hydrogen or a cycloalkyl group with5-7 ring carbon atoms which is optionally substituted, preferably in the1-position, by optionally protected amino, acylamino, wherein acyl aboveall represents the acyl radical of a carbonic acid half-ester, such as alower alkoxycarbonyl, 2-halogeno-lower alkoxycarbonyl or phenyl-loweralkoxycarbonyl radical, or a sulphoamino group which is optionallypresent in the form of a salt, for example in the form of an alkalimetal salt, a phenyl, naphthyl or tetrahydronaphthyl group which isoptionally substituted, preferably by hydroxyl, lower alkoxy, forexample methoxy, acyloxy, wherein acyl above all represents the acylradical of a carbonic acid half-ester, such as a lower alkoxycarbonyl,2-halogeno-lower alkoxycarbonyl or phenyllower alkoxycarbonyl radical,and/or halogen, for example chlorine, a heterocyclic group which isoptionally substituted, for example by lower alkyl, for example methyland/or phenyl, which can in turn carry substituents, such as halogen,for example chlorine, such as a 4-isoxazolyl group, or an amino groupwhich is preferably N-substituted, for example by an optionallysubstituted lower alkyl radical, such as a lower alkyl radicalcontaining halogen, for example chlorine, or n represents 1, R^(I)represents a lower alkyl group which is optionally substituted,preferably by halogen, such as chlorine, by phenyloxy which isoptionally substituted, such as phenyloxy containing hydroxyl, acyloxy,wherein acyl has the abovementioned meaning, and/or halogen, for examplechlorine, or by optionally protected amino and/or carboxyl, for examplea 3-amino-3-carboxypropyl radical which has an optionally protectedamino and/or carboxyl group, for example a silylated, such as tri-loweralkylsilylated, for example trimethylsilylated, amino or acylamino, suchas lower alkanoylamino, halogeno-lower alkanoylamino or phthaloylaminogroup, and/or a silylated, such as tri-lower alkylsilylated, for exampletrimethylsilylated, carboxyl group, or an esterified carboxyl group,such as a carboxyl group which is esterified by lower alkyl,2-halogeno-lower alkyl or phenyl-lower alkyl, for examplediphenylmethyl, or represents a lower alkenyl group, a phenyl groupwhich is optionally substituted, such as a phenyl group which optionallycontains hydroxyl which is acylated, for example as indicated above,and/or halogen, for example chlorine, and also amino-lower alkyl, suchas aminomethyl, which is optionally protected, for example acylated asindicated above, or phenyloxy, which possesses hydroxyl which isoptionally acylated, for example as indicated above, and/or halogen, forexample chlorine, or represents a pyridyl group, for example 4-pyridylgroup, pyridinium group, for example 4-pyridinium group, thienyl group,for example 2-thienyl group, furyl group, for example 2-furyl group,imidazolyl group, for example 1-imidazolyl group, or tetrazolyl group,for example 1-tetrazolyl group, which are optionally substituted, forexample by lower alkyl, such as methyl, or by amino or aminomethyl whichare optionally protected, for example acylated as indicated above, orrepresents an optionally substituted lower alkoxy group, for example amethoxy group, a phenyloxy group which is optionally substituted, suchas a phenyloxy group which contains optionally protected hydroxyl, forexample hydroxyl acylated as indicated above, and/or halogen, such aschlorine, or represents a lower alkylthio group, for example n-butylthiogroup, or lower alkenylthio group, for example allylthio group, aphenylthio, pyridylthio, for example 4-pyridylthio, 2-imidazolylthio,1,2,4-triazol-3-ylthio, 1,3,4-triazol-2-ylthio,1,2,4-triadiazol-3-ylthio, such as 5-methyl-1,2,4-thiadiazol-3-ylthio,1,3,4-thiadiazol-2-ylthio, such as methyl-1,3,4-thiadiazol-2-yl-thio, or5-tetrazolylthio, such as 1-methyl-5-tetrazolylthio group, which areoptionally substituted, for example by lower alkyl, such as methyl, orrepresents a halogen atom, especially chlorine or bromine atom, anoptionally functionally modified carboxyl group, such as loweralkoxycarbonyl, for example methoxycarbonyl or ethoxycarbonyl, nitrileor carbamoyl which is optionally N-substituted, for example by loweralkyl, such as methyl or phenyl, or represents an optionally substitutedlower alkanoyl group, for example an acetyl or propionyl group, or abenzoyl group, or an azido group, and R^(II) and R_(III) representhydrogen, or n represents 1, R^(I) represents lower alkyl or a phenyl,furyl, for example 2-furyl, thienyl, for example 2- or 3-thienyl, orisothiazolyl, for example 4-isothiazolyl group which is optionallysubstituted, such as substituted by hydroxyl which is optionallyacylated, for example as indicated above, and/or by halogen, for examplechlorine, and also represents a 1,4-cyclohexadienyl group, R^(II)represents optionally protected or substituted amino, for example amino,acylamino, such as lower alkoxycarbonylamino, 2-halogeno-loweralkoxycarbonylamino or optionally substituted phenyl-loweralkoxycarbonylamino such as phenyl-lower alkoxycarbonylamino whichcontains lower alkoxy, for example methoxy, or nitro, for exampletert.-butoxycarbonylamino, 2,2,2-trichloroethoxycarbonylamino,4-methoxybenzyloxycarbonylamino or diphenylmethyloxycarbonylamino,arylsulphonylamino, for example 4-methylphenylsulphonylamino,tritylamino, arylthioamino, such as nitrophenylthioamino, for example2-nitrophenylthioamino, or tritylthioamino or 2-propylideneamino whichis optionally substituted, such as 2-propylideneamino which containslower alkoxycarbonyl, for example ethoxycarbonyl, or lower alkanoyl, forexample acetyl, such as 1-ethoxycarbonyl-2-propylideneamino, oroptionally substituted carbamoylamino, such as guanidinocarbonylamino,or a sulphoamino group which is optionally present in the form of asalt, for example in the form of an alkali metal salt, an azido group, acarboxyl group which is optionally present in the form of a salt, forexample in the form of an alkali metal salt, or in a protected form,such as in an esterified form, for example as a lower alkoxycarbonylgroup, for example a methoxycarbonyl group or a ethoxycarbonyl group, oras a phenyloxycarbonyl group, for example a diphenylmethoxycarbonylgroup, a nitrile group, a sulpho group, an optionally functionallymodified hydroxyl group, wherein functionally modified hydroxyl inparticular represents acyloxy, such as formyloxy, as well as loweralkoxycarbonyloxy, 2-halogeno-lower alkoxycarbonyloxy or phenyl-loweralkoxycarbonyloxy which is optionally substituted, such as phenylloweralkoxycarbonyloxy which contains lower alkoxy, for example methoxy, ornitro, for example tert.-butoxycarbonyloxy,2,2,2-trichloroethoxycarbonyloxy, 4-methoxybenzyloxycarbonyloxy ordiphenylmethoxycarbonyloxy, or optionally substituted lower alkoxy, forexample methoxy or phenyloxy, a O-lower alkyl-phosphono group orO,O'-di-lower alkyl-phosphono group, for example O-methyl-phosphono orO,O'-dimethylphosphono, or a halogen atom, for example chlorine orbromine, and R^(III) represents hydrogen, or n represents 1, R^(I) andR^(II) each represent halogen, for example bromine, or loweralkoxycarbonyl, for example methoxycarbonyl, and R^(III) representshydrogen, or n represents 1, R^(I) represents a phenyl, furyl, forexample 2-furyl, or thienyl, for example 2- or 3-thienyl, orisothiazolyl, for example 4-isothiazolyl, group, which are optionallysubstituted, for example by hydroxyl which is optionally acylated, forexample as indicated above, and/or by halogen, for example chlorine, andalso represents a 1,4-cyclohexadienyl group, R^(II) representsaminomethyl which is optionally protected, for example as indicatedabove, and R^(III) represents hydrogen or n represents 1 and each of thegroups R^(I), R^(II) and R^(III) represents lower alkyl, for examplemethyl.

Such acyl radicals Ac are, for example, formyl, cyclopentylcarbonyl,α-aminocyclopentylcarbonyl or α-aminocyclohexylcarbonyl (with anoptionally substituted amino group, for example a sulphoamino groupoptionally present in the form of a salt, or an amino group which issubstituted by an acyl radical which can be split off, preferablyeasily, for example on treatment with an acid agent, such astrifluoroacetic acid, or by reduction, for example on treatment with achemical reducing agent, such as zinc in the presence of aqueous aceticacid, or catalytic hydrogen, or hydrolytically, or an acyl radical whichcan be converted into such a radical, preferably a suitable acyl radicalof a carbonic acid half-ester, such as lower alkoxycarbonyl, for exampletert.-butoxycarbonyl, 2-halogeno-lower alkylcarbonyl, for example2,2,2-trichloroethoxycarbonyl, 2-bromoethoxycarbonyl or2-iodoethoxycarbonyl, arylcarbonylmethoxycarbonyl, for examplephenacyloxycarbonyl, optionally substituted phenyl-lower alkoxycarbonyl,such as phenyl-lower alkoxycarbonyl containing lower alkoxy, for examplemethoxy, or nitro, for example 4-methoxybenzyloxycarbonyl ordiphenylmethoxycarbonyl, or of a carbonic acid half-amide, such ascarbamoyl or N-substituted carbamoyl, such as N-lower alkylcarbamoyl,for example N-methylcarbamoyl, as well as by trityl, also by arylthio,for example 2-nitrophenylthio, arylsulphonyl, for example4-methylphenylsulphonyl or 1-lower alkoxycarbonyl-2-propylidene, forexample 1-ethoxycarbonyl-2-propylidene), 2,6-dimethoxybenzoyl,5,6,7,8-tetrahydronaphthoyl, 2-methoxy-1-naphthoyl,2-ethoxy-1-naphthoyl, benzyloxycarbonyl, hexahydrobenzyloxycarbonyl,5-methyl-3-phenyl-4-isoxazolylcarbonyl,3-(2-chlorophenyl)-5-methyl-4-isoxazolylcarbonyl,3-(2,6-dichlorophenyl)-5-methyl-4-isoxazolylcarbonyl,2-chloroethylaminocarbonyl, acetyl, propionyl, butyryl, pivaloyl,hexanoyl, octanoyl, acrylyl, crotonyl, 3-butenoyl, 2-pentenoyl,methoxyacetyl, butylthioacetyl, allylthioacetyl, methylthioacetyl,chloroacetyl, bromoacetyl, dibromoacetyl, 3-chloropropionyl,3-bromopropionyl, aminoacetyl or 5-amino-5-carboxy-valeryl (with anamino group which is optionally substituted, for example as indicated,such as substituted by a monoacyl or diacyl radical, for example anoptionally halogenated lower alkanoyl radical, such as acetyl ordichloroacetyl, or phthaloyl, and/or with an optionally functionallymodified carboxyl group, for example a carboxyl group present in theform of a salt, such as a sodium salt, or in the form of an ester, suchas a lower alkyl ester, for example a methyl or ethyl ester, or anaryl-lower alkyl ester, for example diphenylmethyl ester), azidoacetyl,carboxyacetyl, methoxycarbonylacetyl, ethoxycarbonylacetyl,bismethoxycarbonylacetyl, N-phenylcarbamoylacetyl, cyanoacetyl,α-cyanopropionyl, 2-cyano-3,3-dimethyl-acrylyl, phenylacetyl,α-bromophenylacetyl, α-azido-phenylacetyl, 3-chlorophenylacetyl, 2- or4-aminomethylphenyl-acetyl (with an amino group which is optionallysubstituted, for example, as indicated), phenacylcarbonyl,phenoxyacetyl, 4-trifluoromethylphenoxyacetyl, benzyloxyacetyl,phenylthioacetyl, bromophenylthioacetyl, 2-phenoxypropionyl,α-phenoxyphenylacetyl, α-methoxyphenylacetyl, α-ethoxy-phenylacetyl,α-methoxy-3,4-dichlorophenylacetyl, α-cyano-phenylacetyl, especiallyphenylglycyl, 4-hydroxyphenylglycyl, 3-chloro-4-hydroxyphenylglycyl,3,5-dichloro-4-hydroxy-phenylglycyl,α-amino-α-(1,4-cyclohexadienyl)-acetyl,α-amino-α-(1-cyclohexenyl)-acetyl, α-aminomethyl-α-phenylacetyl orα-hydroxyphenylacetyl, (it being possible, in these radicals, for anamino group which is present to be optionally substituted, for exampleas indicated above, and/or an aliphatic and/or phenolically bondedhydroxyl group which is present to be optionally protected, analogouslyto the amino group, for example by a suitable acyl radical, especiallyby formyl or by an acyl radical of a carbonic acid half-ester), orα-O-methyl-phosphono-phenylacetyl orα-O,O-dimethyl-phosphono-phenylacetyl, also benzylthioacetyl,benzylthiopropionyl, α-carboxyphenylacetyl (with a carboxyl group whichis optionally functionally modified, for example as indicated above),3-phenylpropionyl, 3-(3-cyanophenyl)-propionyl,4-(3-methoxyphenyl)-butyryl, 2-pyridylacetyl, 4-amino-pyridiniumacetyl(optionally with an amino group which is substituted, for example asindicated above), 2-thienylacetyl, 3-thienylacetyl,2-tetrahydrothienylacetyl, 2-furylacetyl, 1-imidazolylacetyl,1-tetrazolylacetyl, α-carboxy-2-thienylacetyl orα-carboxy-3-thienylacetyl (optionally with a carboxyl group which isfunctionally modified, for example as indicated above),α-cyano-2-thienylacetyl, α-amino-α-(2-thienyl)-acetyl,α-amino-α-(2-furyl)-acetyl or α-amino-α-(4-isothiazolyl)-acetyl(optionally with an amino group which is substituted, for example asindicated above), α-sulphophenylacetyl (optionally with a sulpho groupwhich is functionally modified, for example like the carboxyl group),3-methyl-2-imidazolylthioacetyl, 1,2,4-triazol-3-yl-thioacetyl,1,3,4-triazol-2-ylthioacetyl, 5 -methyl-1,2,4-thiadiazol-3-ylthioacetyl,5-methyl-1,3,4-thiadiazol-2-ylthioacetyl or1-methyl-5-tetrazolylthioacetyl.

An easily removable acyl radical Ac, especially of a carbonic acidhalf-ester, is above all an acyl radical of a half-ester of carbonicacid which can be split off by reduction, for example on treatment witha chemical reducing agent, or by treatment with acid, for example withtrifluoroacetic acid, such as a lower alkoxycarbonyl group whichpreferably has multiple branching and/or an aromatic substituent on thecarbon atom in the α-position to the oxy group, or a methoxycarbonylgroup which is substituted by arylcarbonyl, especially benzoyl,radicals, or a lower alkoxycarbonyl radical which is substituted in theβ-position by halogen atoms, for example tert.-butoxycarbonyl,tert.-pentoxycarbonyl, phenacyloxycarbonyl,2,2,2-trichloroethoxycarbonyl or 2-iodoethoxycarbonyl or a radical whichcan be converted into the latter, such as 2-chloroethoxycarbonyl or2-bromoethoxycarbonyl, and also preferably polycycliccycloalkoxycarbonyl, for example adamantyloxycarbonyl, optionallysubstituted phenyllower alkoxycarbonyl, above all α-phenyl-loweralkoxycarbonyl, wherein the α-position is preferably polysubstituted,for example diphenylmethoxycarbonyl, orα-4-diphenylyl-α-methylethoxycarbonyl, or furyl-lower alkoxycarbonyl,above all α-furyl-lower alkoxycarbonyl, for example furfuryloxycarbonyl.

A bivalent acyl group formed by the two radicals R₁ ^(A) and R₁ ^(b) is,for example, the acyl radical of a lower alkanedicarboxylic acid orlower alkenedicarboxylic acid, such as succinyl, or ano-arylenedicarboxylic acid, such as phthaloyl.

A further bivalent radical formed by the groups R₁ ^(A) and R₁ ^(b) is,for example, a 1-oxo-3-aza-1,4-butylene radical which is substituted,especially in the 2-position and contains, for example, optionallysubstituted phenyl or thienyl, and is optionally monosubstituted ordisubstituted by lower alkyl, such as methyl, in the 4-position, forexample 4,4-dimethyl-2-phenyl-1-oxo-3-aza-1,4-butylene.

An etherified hydroxyl group R₂ ^(A) forms, together with the carbonylgrouping, an esterified carboxyl group which can preferably be spliteasily or can be converted easily into another functionally modifiedcarboxyl group, such as into a carbamoyl or hydrazinocarbonyl group.Such a group R₂ ^(A) is, for example, lower alkoxy, such as methoxy,ethoxy, n-propoxy or isopropoxy, which, together with the carbonylgrouping, forms an esterified carboxyl group, which can easily beconverted, especially in 2-cephem compounds, into a free carboxyl groupor into another functionally modified carboxyl group.

An etherified hydroxyl group R₂ ^(A) which together with a --C(═O)--grouping forms an esterified carboxyl group which can be splitparticularly easily represents, for example, 2-halogeno-lower alkoxy,wherein halogen preferably has an atomic weight above 19. Such a radicalforms, together with the --C(═O)-- grouping, an esterified carboxylgroup which can easily be split on treatment with chemical reducingagents under neutral or weakly acid conditions, for example with zinc inthe presence of aqueous acetic acid, or an esterified carboxyl groupwhich can easily be converted into such a group and is, for example,2,2,2-trichloroethoxy or 2-iodoethoxy, also 2-chloroethoxy or2-bromoethoxy, which can easily be converted into the latter.

An etherified hydroxyl group R₂ ^(A) which together with the --C(═O)--grouping represents an esterified carboxyl group which can also be spliteasily on treatment with chemical reducing agents under neutral orweakly acid conditions, for example on treatment with zinc in thepresence of aqueous acetic acid, and also on treatment with a suitablenucleophilic reagent, for example sodium thiophenolate, is anarylcarbonylmethoxy group, wherein aryl in particular represents anoptionally substituted phenyl group, and preferably phenacyloxy.

The group R₂ ^(A) can also represent an arylmethoxy group wherein arylin particular denotes a monocyclic, preferably substituted, aromatichydrocarbon radical. Such a radical forms, together with the --C(═O)--grouping, an esterified carboxyl group which can easily be split onirradiation, preferably with ultraviolet light, under neutral or acidconditions. An aryl radical in such an arylmethoxy group is inparticular lower alkoxyphenyl, for example methoxyphenyl (whereinmethoxy, above all is in the 3-, 4- and/or 5-position) and/or above allnitrophenyl (wherein nitro is preferably in the 2-position). Suchradicals are, in particular, lower alkoxy-benzyloxy, for examplemethoxy-benzyloxy, and/or nitro-benzyloxy, above all 3- or4-methoxybenzyloxy, 3,5-dimethoxy-benzyloxy, 2-nitro-benzyloxy or4,5-dimethoxy-2-nitro-benzyloxy.

An etherified hydroxyl group R₂ ^(A) can also represent a radical which,together with the --C(═O)-- grouping, forms an esterified carboxyl groupwhich can easily be split under acid conditions, for example ontreatment with trifluoroacetic acid or formic acid. Such a radical isabove all a methoxy group in which methyl is polysubstituted byoptionally substituted hydrocarbon radicals, especially aliphatic oraromatic hydrocarbon radicals, such as lower alkyl, for example methyl,and/or phenyl, or is monosubstituted by a carbocyclic aryl grouppossessing electron-donating substituents or by a heterocyclic group ofaromatic character possessing oxygen or sulphur as a ring member, or inwhich methyl denotes a ring member in a polycycloaliphatic hydrocarbonradical or denotes the ring member which represents the α-position tothe oxygen or sulphur atom in an oxacycloaliphatic or thiacycloaliphaticradical.

Preferred polysubstituted methoxy groups of this nature are tert.-loweralkoxy, for example, tert.-butoxy or tert.-pentoxy, optionallysubstituted diphenylmethoxy, for example diphenylmethoxy or4,4'-dimethoxy-diphenylmethoxy, and also 2-(4-biphenylyl)-2-propoxy,whilst a methoxy group which contains the abovementioned substitutedaryl group or the heterocyclic group is, for example, α-loweralkoxyphenyl-lower alkoxy, such as 4-methoxybenzyloxy or3,4-dimethoxybenzyloxy, or furfuryloxy, such as 2-furfuryloxy. Apolycycloaliphatic hydrocarbon radical in which the methyl of themethoxy group represents a branched, preferably triply branched, ringmember, is, for example, adamantyl, such as 1-adamantyl, and anabovementioned oxacycloaliphatic or thiacycloaliphatic radical whereinthe methyl of the methoxy group is the ring member which represents theα-position to the oxygen atom or sulphur atom, denotes, for example,2-oxa- or 2-thia-lower alkylene or -lower alkenylene with 5-7 ringatoms, such as 2-tetrahydrofuryl, 2-tetrahydropyranyl or2,3-dihydro-2-pyranyl or corresponding sulphur analogues.

The radical R₂ ^(A) can also represent an etherified hydroxyl groupwhich, together with the --C(═O)-- grouping forms an esterified carboxylgroup which can be split hydrolytically, for example under weakly basicor weakly acid conditions. Such a radical is, preferably, an etherifiedhydroxyl group which forms an activated ester group with the --C(═O)--grouping, such as nitrophenyloxy, for example 4-nitrophenyloxy or2,4-dinitrophenyloxy, nitrophenyl-lower alkoxy, for example4-nitro-benzyloxy, hydroxy-lower alkylbenzyloxy, for example4-hydroxy-3,5-tert.-butyl-benzyloxy, polyhalogenophenyloxy, for example2,4,6-trichlorophenyloxy or 2,3,4,5-pentachlorophenyloxy, and alsocyanomethoxy, as well as acylaminomethoxy, for examplephthaliminomethoxy or succinyliminomethoxy.

The group R₂ ^(A) can also represent an etherified hydroxyl group which,together with the carbonyl grouping of the formula --C(═O)--, forms anesterified carboxyl group which can be split under hydrogenolyticconditions and is, for example, α-phenyl-lower alkoxy, which isoptionally substituted, for example by lower alkoxy or nitro, such asbenzyloxy, 4-methoxybenzyloxy or 4-nitrobenzyloxy.

The group R₂ ^(A) can also be an etherified hydroxyl group which,together with the carbonyl grouping --C(═O)--, forms an esterifiedcarboxyl group which can be split under physiological conditions, aboveall an acyloxymethoxy group, wherein acyl denotes, for example, theradical of an organic carboxylic acid, above all of an optionallysubstituted lower alkanecarboxylic acid, or wherein acyloxymethyl formsthe residue of a lactone. Hydroxyl groups etherified in this way arelower alkanoyloxymethoxy, for example acetoxymethoxy orpivaloyloxymethoxy, amino-lower alkanoyloxymethoxy, especiallyα-amino-lower alkanoyloxymethoxy, for example glycyloxymethoxy,L-valyloxymethoxy, L-leucyloxymethoxy and also phthalidyloxy.

A silyloxy or stannyloxy group R₂ ^(A) preferably contains, assubstituents, optionally substituted aliphatic, cycloaliphatic, aromaticor araliphatic hydrocarbon radicals, such as lower alkyl, halogeno-loweralkyl, cycloalkyl, phenyl or phenyl-lower alkyl groups, or optionallymodified functional groups, such as etherified hydroxyl groups, forexample lower alkoxy groups, or halogen atoms, for example chlorineatoms, and above all represents tri-lower alkylsilyloxy, for exampletrimethylsilyloxy, halogeno-lower alkoxy-lower alkylsilyl, for examplechloromethoxymethylsilyl, or tri-lower alkylstannyloxy, for exampletri-n-butylstannyloxy.

An acyloxy radical R₂ ^(A) which, together with a --C(═O)-- grouping,forms a mixed anhydride group which can be split, preferablyhydrolytically, contains, for example, the acyl radical of one of theabovementioned organic carboxylic acids or carbonic acidhalf-derivatives and is, for example, lower alkanoyloxy which isoptionally substituted, such as by halogen, for example fluorine orchlorine, preferably in the α-position, for example acetoxy, pivalyloxyor trichloroacetoxy, or lower alkoxycarbonyloxy, for examplemethoxycarbonyloxy or ethoxycarbonyloxy.

A radical R₂ ^(A) which, together with a --C(═O)-- grouping, forms anoptionally substituted carbamoyl or hydrazino-carbonyl group is, forexample, amino, lower alkylamino or dilower alkylamino, such asmethylamino, ethylamino, dimethylamino or diethylamino, loweralkyleneamino, for example pyrrolidino or piperidino, oxa-loweralkyleneamino, for example morpholino, hydroxylamino, hydrazino, 2-loweralkylhydrazino or 2,2-di-lower alkylhydrazino, for example2-methylhydrazino or 2,2-dimethylhydrazino.

A lower alkyl group R₃ with up to 7, preferably with up to 4, carbonatoms is preferably methyl, or ethyl, n-propyl, hexyl or heptyl.

The 2-oxa-aliphatic or -cycloaliphatic or 2-thiaaliphatic or-cycloaliphatic hydrocarbon radical R₃ is above all a 1-loweralkoxy-1-lower alkyl or 1-lower alkylthio-1-lower alkyl radical, such as1-methoxy-1-ethyl, 1-ethoxy-1-ethyl, 1-methylthio-1-ethyl or1-ethylthio-1-ethyl, or a 2-oxa- or 2-thia-lower alkylene or -loweralkenylene radical, with 5-7 ring atoms, such as 2-tetrahydrofuryl,2-tetrahydropyranyl or 2,3-dihydro-2-pyranyl or a correspondinganalogous sulphur compound.

Easily removable silyl or stannyl groups R₃ are preferably substitutedby optionally substituted aliphatic, cycloaliphatic, aromatic oraraliphatic hydrocarbon radicals, such as lower alkyl, halogeno-loweralkyl, cycloalkyl, phenyl or phenyl-lower alkyl groups, or optionallyfunctionally modified groups, such as etherified hydroxyl groups, forexample lower alkoxy groups, or halogen atoms, for example chlorineatoms. Representative examples of such groups are above all tri-loweralkylsilyl, such as trimethylsilyl, halogeno-lower alkoxy-loweralkylsilyl, such as chloromethoxymethylsilyl, or tri-lower alkylstannyl,such as tri-n-butylstannyl.

Further easily removable hydroxyl-protective groups R₃ are, for example,α-phenyl-lower alkyl, such as benzyl and diphenylmethyl, whereinpossible substituents of the phenylnuclei are, for example, esterifiedor etherified hydroxyl, such as halogen, for example fluorine, chlorineor bromine, or lower alkoxy, such as methoxy.

Salts are, in particular, those of compounds of the formulae IA and IBhaving an acid grouping, such as a carboxyl, sulpho or phosphono group,above all metal salts or ammonium salts, such as alkali metal salts andalkaline earth metal salts, for example sodium, potassium, magnesium orcalcium salts, as well as ammonium salts with ammonia or suitableorganic amines, possible amines for the salt formation being, above all,aliphatic, cycloaliphatic, cycloaliphatic-aliphatic and araliphaticprimary, secondary or tertiary monoamines, diamines or polyamines, aswell as heterocyclic bases, such as lower alkylamines, for exampletriethylamine, hydroxy-lower alkylamines, for example2-hydroxyethylamine, bis-(2-hydroxyethyl)-amine ortris-(2-hydroxyethyl)-amine, basic aliphatic esters of carboxylic acids,for example 4-aminobenzoic acid 2-diethylaminoethyl ester, loweralkyleneamines, for example 1-ethyl-piperidine, cycloalkylamines, forexample bicyclohexylamine, or benzylamines, for exampleN,N'-dibenzyl-ethylenediamine, and also bases of the pyridine type, forexample pyridine, collidine or quinoline. Compounds of the formulae IAand IB which possess a basic group can also form acid addition salts,for example with inorganic acids, such as hydrochloric acid, sulphuricacid or phosphoric acid, or with suitable organic carboxylic acids orsulphonic acids, for example trifluoroacetic acid or p-toluenesulphonicacid. Compounds of the formulae IA and IB having an acid group and abasic group can also be in the form of inner salts, that is to say inthe form of a zwitter-ion. 1-Oxides of compounds of the formula IAhaving salt-forming groups can also form salts, as described above.

The compounds of the present invention possess valuable pharmacologicalproperties or can be used as intermediate products for the manufactureof such compounds. Compounds of the formula Ia wherein, for example, R₁^(a) represents an acyl radical Ac occurring in pharmacologically activeN-acyl derivatives of 6β-amino-penam-3-carboxylic acid compounds or7β-amino-3-cephem-4-carboxylic acid compounds and R₁ ^(b) representshydrogen, or wherein R₁ ^(a) and R₁ ^(b) together represent a1-oxo-3-aza-1,4-butylene radical which is preferably substituted in the2-position, for example by an aromatic or heterocyclic radical, andpreferably substituted in the 4-position, for example by 2 lower alkyl,such as methyl, R₂ denotes hydroxyl or an etherified hydroxyl group R₂^(A) which, together with the carbonyl group, forms an esterifiedcarboxyl group which can easily be split under physiological conditions,and R₃ denotes lower alkyl, and functional groups which may be presentin an acyl radical R₁ ^(a), such as amino, carboxyl, hydroxyl and/orsulpho, are usually in the free form, or salts of such compounds havingsalt-forming groups, are effective, on parenteral and/or oraladministration, against micro-organisms such as Gram-positive bacteria,for example Staphylococcus aureus, Streptococcus pyogenes andDiplococcus pneumoniae (for example in mice at doses of about 0.001 toabout 0.02 g/kg s.c. or p.o.), and Gram-negative bacteria, for example,Escherichia coli, Salmonella typhimurium, Shigella flexneri, Klebsiellapneumoniae, Enterobacter cloacae, Proteus vulgaris, Proteus rettgeri andProteus mirabilis (for example in mice in doses of about 0.001 to about0.15 g/kg s.c. or p.o.), and especially also againstpenicillin-resistant bacteria, and are of low toxicity. These newcompounds can therefore be used, for example in the form ofantibiotically active preparations, for the treatment of correspondinginfections.

Compounds of the formula IB or 1-oxides of compounds of the formula IA,wherein R₁ ^(a), R₁ ^(b), R₂ and R₃ have the meanings indicated in thecontext of the formula IA, or compounds of the formula IA, wherein R₃has the abovementioned meaning, the radicals R₁ ^(a) and R₁ ^(b)represent hydrogen, or R₁ ^(a) denotes an amino protective groupdifferent from an acyl radical occurring in pharmacologically activeN-acyl derivatives of 6β-amino-penam-3-carboxylic acid compounds or7β-amino-3-cephem-4-carboxylic acid compounds and R₁ ^(b) denoteshydrogen, or R₁ ^(a) and R₁ ^(b) together represent a bivalent aminoprotective group different from a 1-oxo-3-aza-1,4-butylene radical whichis preferably substituted in the 2-position, for example by an aromaticor heterocyclic radical, and preferably substituted in the 4-position,for example by 2 lower alkyl, such as methyl, and R₂ representshydroxyl, or R₁ ^(a) and R₁ ^(b) have the abovementioned meanings, R₂represents a radical R₂ ^(A) which together with the --C(═O)-- groupingforms a protected carboxyl group which can preferably be split easily, acarboxyl group protected in this way being different from a carboxylgroup which can be split physiologically, and R₃ has the abovementionedmeanings, are valuable intermediate products, which can be converted ina simple manner, for example as is described below, into theaforementioned pharmacologically active compounds.

The invention in particular relates to the manufacture of 3-cephemcompounds of the formula IA, wherein R₁ ^(a) denotes hydrogen orpreferably an acyl radical contained in a fermentatively obtainable(that is to say naturally occurring) or biosynthetically,semi-synthetically or total-synthetically obtainable, in particularpharmacologically active, such as highly active, N-acyl derivative of a6β-amino-penam-3-carboxylic acid compound or7β-amino-3-cephem-4-carboxylic acid compound, such as one of theabovementioned acyl radicals of the formula A, in which R^(I), R^(II),R^(III) and n above all have the preferred meanings, R₁ ^(b) representshydrogen, or R₁ ^(a) and R₁ ^(b) together represent a1-oxo-3-aza-1,4-butylene radical which is preferably substituted in the2-position, for example by an aromatic or heterocyclic radical, such asphenyl, and preferably substituted in the 4-position, for example by twolower alkyl, such as methyl, R₂ represents hydroxyl, lower alkoxy whichis optionally monosubstituted or polysubstituted, preferably in theα-position, for example by optionally substituted aryloxy, such as loweralkoxyphenyloxy, for example 4-methoxyphenyloxy, lower alkanoyloxy, forexample acetoxy or pivaloyloxy, α-amino-lower alkanoyloxy, for exampleglycyloxy, L-valyloxy or L-leucyloxy, arylcarbonyl, for example benzoyl,or optionally substituted aryl, such as phenyl, lower alkoxyphenyl, forexample 4-methoxyphenyl, nitrophenyl, for example 4-nitrophenyl, orbiphenylyl, for example 4-biphenylyl, or is monosubstituted orpolysubstituted in the β-position by halogen, for example chlorine,bromine or iodine, such as lower alkoxy, for example methoxy, ethoxy,n-propoxy, isopropoxy, n-butoxy, tert.-butoxy or tert.-pentoxy,bis-phenyloxy-methoxy which is optionally substituted by lower alkoxy,for example bis-4-methoxyphenyloxy-methoxy, lower alkanoyloxy-methoxy,for example acetoxymethoxy or pivaloyloxymethoxy, α-amino-loweralkanoyloxymethoxy, for example glycyloxymethoxy, phenacyloxy,optionally substituted phenyl-lower alkoxy, especially 1-phenyl-loweralkoxy, such as phenylmethoxy, with such radicals being able to contain1-3 phenyl radicals which are optionally substituted, for example bylower alkoxy, such as methoxy, nitro or phenyl, for example benzyloxy,4-methoxy-benzyloxy, 2-biphenylyl-2-propoxy. 4-nitro-benzyloxy,diphenylmethoxy, 4,4'-dimethoxy-diphenylmethoxy or trityloxy, or2-halogenolower alkoxy, for example 2,2,2-trichloroethoxy,2-chloroethoxy, 2-bromoethoxy or 2-iodoethoxy, and also 2-phthalidyloxy,as well as acyloxy, such as lower alkoxycarbonyloxy, for examplemethoxycarbonyloxy or ethoxycarbonyloxy, or lower alkanoyloxy, forexample acetoxy or pivaloyloxy, tri-lower alkylsilyloxy, for exampletrimethylsilyloxy, or amino or hydrazino which is optionallysubstituted, for example, by lower alkyl, such as methyl, or hydroxyl,for example amino, lower alkylamino or di-lower alkylamino, such asmethylamino or dimethylamino, hydrazino, 2-lower alkylhydrazino or2,2-di-lower alkylhydrazino, for example 2-methylhydrazino or2,2-dimethylhydrazino, or hydroxyamino, and R₃ represents hydrogen,lower alkyl, especially methyl or a hydroxyl protective group, such astri-lower alkylsilyl, for example trimethylsilyl, or benzyl ordiphenylmethyl which are optionally substituted, for example by halogenor lower alkoxy, as well as the 1-oxides thereof, and also thecorresponding 2-cephem compounds of the formula IB, or salts of suchcompounds with salt-forming groups.

Above all, in a 3-cephem compound of the formula IA, and in acorresponding 2-cephem compound of the formula IB, and also in a 1-oxideof a 3-cephem compound of the formula IA, or in a salt of such acompound having salt-forming groups, R₁ ^(a) represents hydrogen or anacyl radical contained in fermentatively obtainable (that is to saynaturally occurring) or biosynthetically obtainable N-acyl derivativesof 6β-amino-penam-3-carboxylic acid compounds or7β-amino-3-cephem-4-carboxylic acid compounds, especially of the formulaA, wherein R^(I), R^(II) and R^(III) and n above all have the preferredmeanings, such as a phenylacetyl or phenyloxyacetyl radical which isoptionally substituted, for example by hydroxyl, also a lower alkanoylor lower alkenoyl radical which is optionally substituted, for exampleby lower alkylthio, or lower alkenylthio, as well as by optionallysubstituted, such as acylated, amino and/or functionally modified, suchas esterified, carboxyl, for example 4-hydroxy-phenylacetyl, hexanoyl,octanoyl or n-butylthioacetyl, and especially 5-amino-5-carboxy-valeryl,wherein the amino and/or the carboxyl groups are optionally protectedand are present, for example, as acylamino or esterified carboxyl,phenylacetyl or phenyloxyacetyl, or an acyl radical occurring in highlyactive N-acyl derivatives of 6β-amino-penam-3-carboxylic acid compoundsor 7β-amino-3-cephem-4-carboxylic acid compounds, especially of theformula A, wherein R^(I), R^(II), R^(III) and n above all have thepreferred meanings, such as formyl, 2-halogenoethylcarbamoyl, forexample 2-chloroethylcarbamoyl, cyanoacetyl, phenylacetyl,thienylacetyl, for example 2-thienylacetyl, or tetrazolylacetyl, forexample 1-tetrazolylacetyl, but especially acetyl substituted in theα-position by a cyclic, such as a cycloaliphatic, aromatic orheterocyclic, above all monocyclic, radical and by a functional group,above all amino, carboxyl, sulpho or hydroxyl groups, especiallyphenylglycyl, wherein phenyl represents phenyl which is optionallysubstituted, for example by optionally protected hydroxyl, such asacyloxy, for example optionally halogen-substituted loweralkoxycarbonyloxy or lower alkanoyloxy, and/or by halogen, for examplechlorine, for example phenyl or 3- or 4-hydroxyphenyl,3-chloro-4-hydroxyphenyl or 3,5-dichloro-4-hydroxy-phenyl (optionallyalso with a protected hydroxyl group, such as an acylated hydroxylgroup), and wherein the amino group can also optionally be substitutedand represents, for example, a sulphoamino group optionally present inthe form of a salt, or an amino group which contains, as substituents, ahydrolytically removable trityl group or above all an acyl group, suchas an optionally substituted carbamoyl group, such as an optionallysubstituted ureidocarbonyl group, for example ureidocarbonyl orN'-trichloromethylureidocarbonyl, or an optionally substitutedguanidinocarbonyl group, for example guanidinocarbonyl, or an acylradical which can be split off, preferably easily, for example ontreatment with an acid agent, such as trifluoroacetic acid, orreductively, such as on treatment with a chemical reducing agent, suchas zinc in the presence of aqueous acetic acid, or with catalytichydrogen, or hydrolytically, or an acyl radical which can be convertedinto such a radical, preferably a suitable acyl radical of a carbonicacid half-ester, such as one of the abovementioned, for exampleoptionally halogen-substituted or benzoyl-substituted, loweralkoxycarbonyl radicals, for example tert.-butoxycarbonyl,2,2,2-trichloroethoxycarbonyl, 2-chloroethoxycarbonyl,2-bromoethoxycarbonyl, 2-iodoethoxycarbonyl or phenacyloxycarbonyl,optionally lower alkoxy-substituted or nitro-substituted phenyl-loweralkoxycarbonyl, for example 4-methoxy-benzyloxycarbonyl ordiphenylmethoxycarbonyl, or a suitable acyl radical of a carbonic acidhalf-amide, such as carbamoyl or N-methylcarbamoyl, or an arylthio oraryl-lower alkylthio radical which can be split off with a nucleophilicreagent, such as hydrocyanic acid, sulphurous acid or thioacetic acidamide, for example 2-nitrophenylthio or tritylthio, an arylsulphonylradical which can be split off by means of electrolytic reduction, forexample 4-methylphenylsulphonyl, or a 1-lower alkoxycarbonyl or 1-loweralkanoyl-2-propylidene radical which can be split off with an acidagent, such as formic acid or aqueous mineral acid, for examplehydrochloric acid or phosphoric acid, for example1-ethoxycarbonyl-2-propylidene, and also α-(1-4,cyclohexadienyl)-glycol,α-(1-cyclohexenyl)-glycyl, α-thienyl-glycyl, such as α-2- orα-3-thienylglycyl, α-furylglycyl, such as α-2-furylglycyl,α-isothiazolylglycyl, such as α-4-isothiazolyl-glycyl, it being possiblefor the amino group in such radicals to be substituted or protected, forexample as indicated for a phenylglycyl radical, alsoα-carboxy-phenylacetyl or α-carboxy-thienylacetyl, for exampleα-carboxy-2-thienylacetyl (optionally with a functionally modifiedcarboxyl group, for example a carboxyl group present in the form of asalt, such as a sodium salt, or in the form of an ester, such as a loweralkyl ester, for example methyl or ethyl ester, or phenyl-lower alkylester, for example diphenylmethyl ester), α-sulpho-phenylacetyl(optionally also with a sulpho group which is functionally modified, forexample like the carboxyl group), α-phosphono-, α-O-methyl-phosphono- orα-O,O'-dimethyl-phosphono-phenylacetyl, or α-hydroxy-phenylacetyl(optionally with a functionally modified hydroxyl group, especially withan acyloxy group, wherein acyl denotes an acyl radical which can besplit off, preferably easily, for example on treatment with an acidagent, such as trifluoroacetic acid, or with a chemical reducing agent,such as zinc in the presence of aqueous acetic acid, or an acyl radicalwhich can be converted into such a radical, preferably a suitable acylradical of a carbonic acid half-ester, such as one of the abovementionedlower alkoxycarbonyl radicals which are, for example, optionallysubstituted by halogen or benzoyl, for example2,2,2-trichloroethoxycarbonyl, 2-chloroethoxycarbonyl,2-bromoethoxycarbonyl, 2-iodoethoxycarbonyl, tert.-butoxycarbonyl orphenacyloxycarbonyl, and also formyl), as well as1-amino-cyclohexylcarbonyl, aminomethylphenylacetyl, such as 2- or4-amino-methylphenylacetyl, or amino-pyridiniumacetyl, for example4-amino-pyridiniumacetyl (optionally also with an amino group which issubstituted, for example as indicated above), or pyridylthioacetyl, forexample 4-pyridylthioacetyl, and R₁ ^(b) represents hydrogen, or R₁ ^(a)and R₁ ^(b) together represent a 1-oxo-3-aza-1,4-butylene radical whichis preferably substituted in the 2-position by phenyl which isoptionally substituted by protected hydroxyl, such as acyloxy, forexample optionally halogen-substituted lower alkoxycarbonyloxy or loweralkanoyloxy, and/or by halogen, for example chlorine, for example phenylor 3- or 4-hydroxyphenyl, 3-chloro-4-hydroxyphenyl or3,5-dichloro-4-hydroxy-phenyl (optionally also with a hydroxyl groupwhich is protected, for example acylated as indicated above), and whichoptionally contains two lower alkyl, such as methyl, in the 4-position,and R₂ represents hydroxyl, lower alkoxy, especially α-poly-branchedlower alkoxy, for example tert.-butoxy, also methoxy or ethoxy,2-halogeno-lower alkoxy, for example 2,2,2-trichloroethoxy, 2-iodoethoxyor 2-chloroethoxy or 2-bromoethoxy which can easily be converted into2-iodoethoxy, phenacyloxy, 1-phenyl-lower alkoxy with 1-3 phenylradicals which are optionally substituted by lower alkoxy or nitro, forexample 4-methoxybenzyloxy, 4-nitro-benzyloxy, diphenylmethoxy,4,4'-dimethoxydiphenylmethoxy or trityloxy, lower alkanoyloxymethoxy,for example acetoxymethoxy or pivaloyloxymethoxy, α-amino-loweralkanoyloxymethoxy, for example glycyloxymethoxy,2-phthalidyloxymethoxy, lower alkoxycarbonyloxy, for exampleethoxycarbonyloxy, or lower alkanoyloxy, for example acetoxy, and alsotri-lower alkylsilyloxy, for example trimethylsilyloxy, and R₃represents hydrogen, lower alkyl, especially methyl, or a hydroxylprotective group, such as tri-lower alkylsilyl, for exampletrimethylsilyl, or benzyl or diphenylmethyl which are optionallysubstituted, for example by halogen, such as chlorine or bromine, orlower alkoxy, such as methoxy.

The invention above all relates to the manufacture of 3-cephem compoundsof the formula IA, wherein R₁ ^(a) denotes hydrogen or an acyl group ofthe formula ##STR6## wherein R_(a) denotes phenyl or hydroxyphenyl, forexample 3- or 4-hydroxyphenyl, also hydroxy-chlorophenyl, for example3-chloro-4-hydroxyphenyl or 3,5-dichloro-4-hydroxy-phenyl, it beingpossible for hydroxy substituents in such radicals to be protected byacyl radicals, such as optionally halogenated lower alkoxycarbonylradicals, for example tert.-butoxycarbonyl or2,2,2-trichloroethoxycarbonyl, as well as thienyl, for example 2- or3-thienyl, and also pyridyl, for example 4-pyridyl, aminopyridinium, forexample 4-aminopyridinium, furyl, for example 2-furyl, isothiazolyl, forexample 4-isothiazolyl, or tetrazolyl, for example 1-tetrazolyl, or1,4-cyclohexadienyl or 1-cyclohexenyl, X represents oxygen or sulphur, mrepresents 0 or 1 and R_(b) represents hydrogen, or, if m represents 0 ,R_(b) represents amino, as well as protected amino, such as acylamino,for example α-poly-branched lower alkoxycarbonylamino, such astert.-butoxycarbonylamino, or 2-halogeno-lower alkoxycarbonylamino, forexample 2,2,2-trichloroethoxycarbonylamino, 2-iodoethoxycarbonylamino or2-bromoethoxycarbonylamino, or optionally lower alkoxy-substituted ornitro-substituted phenyl-lower alkoxycarbonylamino, for example4-methoxybenzyloxycarbonylamino or diphenylmethoxycarbonylamino, or3-guanylureido, also sulphoamino or tritylamine, as well asarylthioamino, for example 2-nitrophenylthioamino, arylsulphonylamino,for example 4-methylphenylsulphonylamino, or 1-loweralkoxycarbonyl-2-propylideneamino, for example1-ethoxycarbonyl-2-propylideneamino, carboxyl, or carboxyl present inthe form of a salt, for example an alkali metal salt, such as a sodiumsalt, as well as protected carboxyl, for example esterified carboxyl,such as phenyl-lower alkoxycarbonyl, for examplediphenylmethoxycarbonyl, sulpho, or sulpho present in the form of asalt, for example an alkali metal salt, such as a sodium salt, as wellas protected sulpho, hydroxyl, as well as protected hydroxyl, such asacyloxy, for example α-poly-branched lower alkoxycarbonyloxy, such astert.-butoxycarbonyloxy or 2 -halogeno-lower alkoxycarbonyloxy, such as2,2,2-trichloroethoxycarbonyloxy, 2-iodoethoxycarbonyloxy or2-bromoethoxycarbonyloxy, also formyloxy, or 0-lower alkylphosphono or0,0'-di-lower alkylphosphono, for example 0-methyl-phosphono or0,0'-dimethylphosphono, or denotes a 5-amino-5-carboxy-valeryl radical,wherein the amino and/or carboxyl groups can also be protected and are,for example, present as acylamino, for example lower alkanoylamino, suchas acetylamino, halogeno-lower alkanoylamino such asdichloroacetylamino, benzoylamino or phthaloylamino, or as esterifiedcarboxyl, such as phenyl-lower alkoxycarbonyl, for examplediphenylmethoxycarbonyl, and m preferably denotes 1 if R_(a) representsphenyl, hydroxyphenyl, hydroxychlorophenyl or pyridyl, and m denotes 0and R_(b) differs from hydrogen if R_(a) represents phenyl,hydroxyphenyl, hydroxy-chlorophenyl, thienyl, furyl, isothiazolyl,1,4-cyclohexadienyl or 1-cyclohexenyl, R₁ ^(b) denotes hydrogen, R₂above all represents hydroxyl and also represents lower alkoxy,especially α-poly-branched lower alkoxy, for example tert.-butoxy,2-halogeno-lower alkoxy, for example 2,2,2-trichloroethoxy, 2-iodoethoxyor 2-bromoethoxy, or diphenylmethoxy which is optionally substituted,for example, by lower alkoxy, for example methoxy, for examplediphenylmethoxy or 4,4'-dimethoxydiphenylmethoxy, as well as tri-loweralkylsilyloxy, for example trimethylsilyloxy, and R₃ denotes hydrogen,lower alkyl, for example methyl, ethyl or n-butyl, as well as tri-loweralkylsilyl, for example trimethylsilyl, and benzyl or diphenylmethylwhich is optionally substituted for example by halogen, such as chlorineor bromine, or lower alkoxy, such as methoxy, as well as the 1-oxides ofsuch 3-cephem compounds of the formula IA, and also the corresponding2-cephem compounds of the formula IB, or salts, especiallypharmaceutically usable, non-toxic salts, of such compounds havingsalt-forming groups, such as alkali metal salts, for example sodiumsalts, or alkaline earth metal salts, for example calcium salts, orammonium salts, including those with amines, of compounds wherein R₂represents hydroxyl, and which contain a free amino group in the acylradical of the formula B.

Above all, in 3-cephem compounds of the formula IA, and also incorresponding 2-cephem compounds of the formula IB, as well as in salts,especially in parmaceutically usable non-toxic salts, of such compoundswhich have salt-forming groups, as in the salts mentioned in thepreceding paragraph, R₁ ^(a) represents hydrogen, the acyl radical ofthe formula B wherein R_(a) denotes phenyl, as well as hydroxyphenyl,for example 4-hydroxy-phenyl, thienyl, for example 2- or 3-thienyl,4-isothiazolyl, 1,4-cyclohexadienyl or 1-cyclohexenyl, X denotes oxygen,m denotes 0 or 1 and R_(b) denotes hydrogen, or, if m represents 0,denotes amino, as well as protected amino, such as acylamino, forexample α-poly-branched lower alkoxycarbonylamino, such astert.-butoxycarbonylamino, or 2-halogeno-lower alkoxycarbonylamino, forexample 2,2,2-trichloroethoxycarbonylamino, 2-iodoethoxycarbonylamino or2-bromoethoxycarbonylamino, or optionally lower alkoxy-substituted ornitro-substituted phenyl-lower alkoxycarbonylamino, for example4-methoxybenzyloxycarbonylamino, or hydroxyl, as well as protectedhydroxyl, such as acyloxy, for example α-poly-branched loweralkoxycarbonyloxy, such as tert.-butoxycarbonyloxy, or 2-halogeno-loweralkoxycarbonyloxy, such as 2,2,2-trichloroethoxycarbonyloxy,2-iodoethoxycarbonyloxy or 2-bromoethoxycarbonyloxy, and also formyloxy,or represents a 5-amino-5-carbonyl-valeryl radical, wherein the aminoand carboxyl group can also be protected and, for example, are in theform of acylamino, for example lower alkanoylamino, such as acetylamino,halogeno-lower alkanoylamino, such as dichloroacetylamino, benzoylaminoor phthaloylamino, or of esterified carboxyl, such as phenyl-loweralkoxycarbonyl, for example diphenylmethoxycarbonyl, with m preferablydenoting 1, if R_(a) is phenyl or hydroxyphenyl, R₁ ^(b) representshydrogen, R₂ above all denotes hydroxyl and also lower alkoxy which isoptionally halogen-substituted, for example chlorine-substituted,bromine-substituted or iodine-substituted, in the 2-position, especiallyα-poly-branched lower alkoxy, for example tert.-butoxy, or2-halogeno-lower alkoxy, for example 2,2,2-trichloroethoxy, such asmethoxy-substituted diphenylmethoxy, for example diphenylmethoxy or4,4'-dimethoxy-diphenylmethoxy, or p-nitrobenzyloxy, and also tri-loweralkylsilyloxy, for example trimethylsilyloxy, and R₃ denotes hydrogen,lower alkyl, especially methyl, tri-lower alkylsilyl, for exampletrimethylsilyl, or a benzyl or diphenylmethyl group which is optionallysubstituted by halogen, for example chlorine or bromine, or loweralkoxy, for example methoxy.

The invention above all relates to the manufacture of7β-(D-α-amino-α-R_(a) -acetylamino)-3-lower alkoxy-3-cephem-4-carboxylicacids, wherein R_(a) represents phenyl, 4-hydroxyphenyl, 2-thienyl,1,4-cyclohexadienyl or 1-cyclohexenyl and lower alkoxy contains up to 4carbon atoms and represents, for example, ethoxy or n-butoxy, but aboveall methoxy, and the inner salts thereof, and above all3-methoxy-7β-(D-α-phenyl-glycylamino)-3-cephem-4-carboxylic acid and theinner salt thereof; in the abovementioned concentrations, especially onoral administration, these compounds display excellent antibioticproperties both against Gram-positive and especially againstGram-negative bacteria, and are of low toxicity.

According to the process of the invention, compounds of the formula IA,their 1-oxides, compounds of the formula IB and salts of such compounds,having salt-forming groups, are manufactured by treating a compound ofthe formula ##STR7## wherein R₁ ^(a), R₁ ^(b) and R₂ ^(A) have themeanings mentioned under formula IA, R₃ ^(o) represents lower alkyl or ahydroxyl protective group, and Y represents a group which is removed,with a base, and, if desired, in a resulting compound of the formula IAor IB, converting the protected carboxyl group of the formula--C(═O)--R₂ ^(A) into the free carboxyl group or into another protectedcarboxyl group, and/or, if desired, converting the protected hydroxylgroup --O--R₃ ^(o) into a free hydroxyl group and/or converting theresulting free hydroxyl group or the protected hydroxyl group --O--R₃^(o) into a lower alkoxy group --O--R₃, and/or, if desired, within thedefinition of the end products, converting a resulting compound intoanother compound and/or, if desired, converting a resulting compoundhaving a salt-forming group into a salt or converting a resulting saltinto the free compound or into another salt and/or, if desired,separating a resulting mixture of isomeric compounds into the individualisomers.

In a compound of the formula II, the group --O--R₃ ^(o) can be in thetrans-position (crotonic acid configuration) or in the cis-position(isocrotonic acid configuration) relative to the carboxyl group.

In a starting compound of the formula II, a group Y which is removed is,for example, a --S--R₄ group, a --SO₂ --R₅ group bonded by the sulphuratom to the thio group --S--, or a --S--SO₂ --R₅ group.

In the group --S--R₄, R₄ is an optionally substituted aromaticheterocyclic radical with up to 15, preferably up to 9, carbon atoms,and at least one ring nitrogen atom and optionally a further ringhetero-atom, such as oxygen or sulphur, which radical is bonded to thethio group --S-- by one of its ring carbon atoms, which is bonded to aring nitrogen atom by a double bond. Such radicals are monocyclic orbicyclic and can be substituted, for example by lower alkyl, such asmethyl or ethyl, lower alkoxy, such as methoxy or ethoxy, halogen, suchas fluorine or chlorine, or aryl, such as phenyl.

Such radicals R₄ are, for example, monocyclic five-memberedthiadiazacyclic, thiatriazacyclic, oxadiazacyclic or oxatriazacyclicradicals of aromatic character, but especially monocyclic five-membereddiazacyclic, oxazacyclic and thiazacyclic radicals of aromaticcharacter, and/or, above all, the corresponding benzdiazacyclic,benzoxazacyclic or benzthiazacyclic radicals, wherein the heterocyclicpart is five-membered and is of aromatic character, and in radicals R₄ asubstitutable ring nitrogen atom can be substituted, for example, bylower alkyl. Representative examples of such groups R₄ are1-methyl-imidazol-2-yl, 1,3-thiazol-2-yl, 1,3,4-thiadiazol-2-yl,1,3,4,5-thiatriazol-2-yl, 1,3-oxazol-2-yl, 1,3,4-oxadiazol-2-yl,1,3,4,5-oxatriazol-2-yl, 2-quinolyl, 1-methyl-benzimidazol-2-yl,benzoxazol-2-yl and especially benzthiazol-2-yl. Further groups R₄ areacyl radicals of organic carboxylic acids or thiocarboxylic acids, suchas optionally substituted aliphatic, cycloaliphatic, araliphatic oraromatic acyl or thioacyl groups with up to 18, preferably with up to10, carbon atoms, such as lower alkanoyl, for example acetyl orpropionyl, lower thioalkanoyl, for example thioacetyl or thiopropionyl,cycloalkanecarbonyl, for example cyclohexanecarbonyl,cycloalkanethiocarbonyl, for example cyclohexanethiocarbonyl, benzoyl,thiobenzoyl, naphthylcarbonyl, naphthylthiocarbonyl, heterocycliccarbonyl or thiocarbonyl, such as 2-, 3- or 4-pyridylcarbonyl, 2- or3-thenoyl, 2- or 3-furoyl, 2-, 3- or 4-pyridylthiocarbonyl, 2- or3-thiothenoyl, or 2- or 3-thiofuroyl, or corresponding substituted acylor thioacyl groups, for example acyl or thioacyl groups monosubstitutedor polysubstituted by lower alkyl, such as methyl, halogen, such asfluorine or chlorine, lower alkoxy, such as methoxy, aryl, such asphenyl, or aryloxy, such as phenyloxy.

In the groups --SO₂ --R₅ and --S--SO₂ --R₅, R₅ is an optionallysubstituted, especially an aliphatic, cycloaliphatic, araliphatic oraromatic, hydrocarbon radical with up to 18, preferably with up to 10,carbon atoms. Suitable groups R₅ are, for example, optionallysubstituted, such as lower alkoxy-, such as methoxy-, halogen-, such asfluorine-, chlorine- or bromine-, aryl-, such as phenyl-, or aryloxy-,such as phenyloxy-monosubstituted or -polysubstituted alkyl groups,especially lower alkyl groups, such as methyl, ethyl or butyl groups,alkenyl groups, such as allyl or butenyl groups, cycloalkyl groups, suchas cyclopentyl or cyclohexyl groups, or naphthyl or especially phenylgroups which are optionally monosubstituted or polysubstituted by loweralkyl, such as methyl, lower alkoxy, such as methoxy, halogen, such asfluorine, chlorine or bromine, aryl, such as phenyl, aryloxy, such asphenyloxy, or nitro, for example phenyl, o-, m- or preferably p-tolyl,o-, m- or preferably p-methoxyphenyl, o-, m- or p-chlorophenyl,p-biphenylyl, p-phenoxyphenyl, p-nitrophenyl or 1- or 2-naphthyl. In astarting material of the formula II, R₂ ^(A) preferably represents anetherified hydroxyl group which, with the --C(═O)-- grouping, forms anesterified carboxyl group which can be split, especially under mildconditions, it being possible for functional groups which may be presentin a carboxyl protective group R₂ ^(A) to be protected in a manner whichis in itself known, for example as indicated above. A group R₂ ^(A) is,for example, in particular an optionally halogen-substituted loweralkoxy group, such as methoxy, α-poly-branched lower alkoxy, for exampletert.-butoxy, or 2-halogeno-lower alkoxy, wherein halogen represents,for example, chlorine, bromine or iodine, above all2,2,2-trichloroethoxy, 2-bromoethoxy, or 2-iodoethoxy, or an optionallysubstituted 1-phenyl-lower alkoxy group, such as a 1-phenyl-lower alkoxygroup which contains lower alkoxy, for example methoxy, or nitro, suchas benzyloxy or diphenylmethoxy which are optionally substituted, forexample as indicated, for example benzyloxy, 4-methoxybenzyloxy,4-nitrobenzyloxy, diphenylmethoxy or 4,4'-dimethoxy-diphenylmethoxy, andalso an organic silyloxy or stannyloxy group, such as tri-loweralkylsilyloxy, for example trimethylsilyloxy, or halogen, for examplechlorine. Preferably, in a starting material of the formula II, theradical R₁ ^(a) denotes an amino protective group R₁ ^(A), such as anacyl group Ac, in which free functional groups which may be present, forexample amino, hydroxyl, carboxyl or phosphono groups, can be protectedin a manner which is in itself known, amino groups, for example, by theabovementioned acyl, trityl, silyl or stannyl radicals as well assubstituted thio or sulphonyl radicals, and hydroxyl, carboxyl orphosphono groups, for example, by the abovementioned ether or estergroups, including silyl or stannyl groups, and R₁ ^(b) denotes hydrogen.

In a starting material of the formula II, R₃ ^(o) preferably denoteslower alkyl, especially methyl, or, as a hydroxyl protective group,preferably a substituted silyl group, especially the trimethylsilylgroup, as well as an α-phenyl-lower alkyl group, such as the benzyl ordiphenylmethyl group.

Suitable bases for the cyclisation reaction are, in particular, strongorganic or inorganic bases. Bases to be singled out particularly arebicyclic amidines, such as diazabicycloalkenes, for example1,5-diazabicyclo[4.3.0]non-5-ene or 1,5-diazabicyclo[5.4.0]undec-5-ene,substituted guanidines, for example guanidines polysubstituted by loweralkyl, such as tetramethylguanidine, and also metal bases, such ashydride, amides or alcoholates of alkali metals, especially of lithium,sodium or potassium, for example sodium hydride, lithium di-loweralkylamides, such as lithium diisopropylamide and potassium loweralkanolates, such as potassium tert.-butylate. Compounds of the formulaII, in which R₂ ^(A) denotes halogen, for example chlorine, can also becyclised with a tertiary organic nitrogen base, for example a tri-loweralkylamine, such as triethylamine, and in the presence of an alcohol,such as a lower alkanol, for example tert.-butanol, the correspondingester of the formula IA and/or IB can be obtained.

The reaction according to the invention is carried out in a suitableinert solvent, for example in an aliphatic, cycloaliphatic or aromatichydrocarbon, such as hexane, cyclohexane, benzene or toluene, ahalogenated hydrocarbon, such as methylene chloride, an ether, such as adi-lower alkyl ether, for example diethyl ether, a di-lower alkoxy-loweralkane, such as dimethoxyethane, a cyclic ether, such as dioxane ortetrahydrofurane, or a lower alkanol, for example methanol, ethanol ortert.-butanol, or a mixture thereof, at room temperature of with slightwarming to 40°-50°, if desired in an inert gas atmosphere, such as anitrogen atmosphere.

When treating a compound of the formula II, wherein Y denotes a --S--R₄group, for example the 2-benzthiazolylthio radical, with one of thebases mentioned, for example with 1,5-diazabicyclo[5.4.0]undec-5-ene,the yield of compounds of the formula IA and IB can be increased byadding a sulphinic acid of the formula H--SO₂ --R₅, for examplep-toluenesulphinic acid.

In the cyclisation reaction according to the invention it is possible,depending on the starting material and reaction conditions, to obtainsingle compounds of the formula IA or IB or mixtures of compounds of theformula IA and IB. Suitable mixtures can be separated in a manner whichis in itself known, for example with the aid of suitable methods ofseparation, for example by adsorption and fraction elution, includingchromatography (column, paper or plate chromatography) using suitableadsorbents, such as silica gel or aluminum oxide, and eluting agents,and also by fractional crystallisation, solvent distribution and thelike.

Resulting compounds of the formulae IA and IB which are suitableintermediates for the manufacture of pharmacologically more active endproducts can be converted into such active end products by variousadditional measures which are in themselves known.

In a compound, obtainable according to the invention, of the formulae IAor IB, a hydroxyl protective group R₃ can easily be split off andreplaced by hydrogen. A 2-oxa-aliphatic or -cycloaliphatic or2-thia-aliphatic or -cycloaliphatic hydrocarbon radical can, forexample, be split off by acid hydrolysis and a silyl or stannyl group byhydrolysis, alcoholysis or acidolysis, for example by treatment withwater or with an alcohol, such as methanol or ethanol, or with an acid,such as acetic acid.

The splitting off of an optionally substituted α-phenyl-lower alkylgroup, for example benzyl group or diphenylmethyl group, is effected,for example, by acidolysis, for example by treatment with a suitableinorganic or organic acid, such as hydrochloric acid, sulphuric acid,formic acid or especially trifluoroacetic acid, or by hydrogenolysis,for example by treatment with hydrogen in the presence of a catalyst,such as palladium. The resulting 3-hydroxy compounds are in the main inthe 3-cephem form. The splitting off of a hydroxyl protective group R₃can optionally be carried out selectively, that is to say without acarboxyl protective group R₂ ^(A) being split off at the same time.

Enol-ethers, that is to say compounds of the formula

Enol-ethers, that is to say compounds of the formula IA and/or IB,wherein R₃ represents lower alkyl, are obtained from compounds of theformulae IA or IB, wherein R₃ is a radical which protects hydroxylgroups, by replacing this radical by hydrogen and subsequentlyetherifying the free hydroxyl group in accordance with any processsuitable for the etherification of enol groups. Preferably, theetherifying reagent used is a diazo compound of the formula R₃ -N₂corresponding to the optionally substituted hydrocarbon radical R₃,above all an optionally substituted diazo-lower alkane, for examplediazomethane, diazoethane or diazo-n-butane, or an optionallysubstituted α-phenyl-diazo-lower alkane, for example phenyldiazomethaneor diphenyldiazomethane. These reagents are used in the presence of asuitable inert solvent, such as an aliphatic, cycloaliphatic or aromatichydrocarbon, such as hexane, cyclohexane, benzene or toluene, of ahalogenated aliphatic hydrocarbon, for example methylene chloride, of alower alkanol, for example methanol, ethanol or tert.-butanol, or of anether, such as of a dilower alkyl-ether, for example diethyl ether, orof a cyclic ether, for example tetrahydrofurane or dioxane, or of asolvent mixture and, depending on the diazo reagent, with cooling, atroom temperature or with slight warming and also, if necessary, in aclosed vessel and/or under an inert gas atmosphere, for example anitrogen atmosphere.

Furthermore, enol-ethers of the formula IA and/or IB can be formed bytreatment with a reactive ester of an alcohol of the formula R₃ -OHwhich corresponds to the lower alkyl radical or the optionallysubstituted α-phenyl-lower alkyl, for example benzyl or diphenylmethyl,radical R₃. Suitable esters are above all those with strong inorganic ororganic acids, such as mineral acids, for example hydrogen halide acids,such as hydrochloric acid, hydrobromic acid or hydriodic acid, alsosulphuric acid or halogeno-sulphuric acids, for example fluorosulphuricacid, or strong organic sulphonic acids, such as lower alkanesulphonicacids which are optionally substituted, for example by halogen, such asfluorine, or aromatic sulphonic acids, such as, for example,benzenesulphonic acids which are optionally substituted, for example bylower alkyl, such as methyl, halogen, such as bromine, and/or nitro, forexample methanesulphonic acid, trifluoromethanesulphonic acid orp-toluenesulphonic acid. These reagents, especially di-lower alkylsulphates, such as dimethyl sulphate, and also lower alkylfluorosulphates, for example methyl fluorosulphate, or optionallyhalogen-substituted methanesulphonic acid lower alkyl esters, forexample trifluoromethanesulphonic acid methyl ester, are usuallyemployed in the presence of a solvent, such as of an optionallyhalogenated, such as chlorinated, aliphatic, cycloaliphatic or aromatichydrocarbon, for example methylene chloride, of an ether, such asdioxane or tetrahydrofurane, or of a lower alkanol, such as methanol, orof a mixture. At the same time, suitable condensation agents arepreferably employed, such as alkali metal carbonates or bicarbonates,for example sodium carbonate or bicarbonate or potassium carbonate orbicarbonate (usually together with a sulphate) or organic bases such as,usually sterically hindered, tri-lower alkylamines, for exampleN,N-diisopropyl-N-ethyl-amine (preferably together with lower alkylhalogenosulphates or optionally halogen-substituted methanesulphonicacid lower alkyl esters), the reaction being carried out with cooling,at room temperature or with warming, for example at temperatures ofabout -20° C. to about 50° C. and, if necessary, in a closed vesseland/or in an inert gas atmosphere, for example a nitrogen atmosphere.

Enol-ethers can also be manufactured by treatment with a compoundcontaining two or three etherified hydroxyl groups of the formula R₃ -O-on the same carbon atom of aliphatic character, that is to say bytreatment with an appropriate acetal or ortho-ester, in the presence ofan acid agent. Thus, for example, it is possible to use, as etherifyingagents, gem-lower alkoxy-lower alkanes, such as 2,2-dimethoxy-propane,in the presence of a strong organic sulphonic acid, such asp-toluenesulphonic acid, and of a suitable solvent, such as of a loweralkanol, for example methanol, or of a di-lower alkylsulphoxide or loweralkylenesulphoxide, for example dimethylsulphoxide, or orthoformic acidtri-lower alkyl esters, for example orthoformic acid triethyl ester, inthe presence of a strong mineral acid, for example sulphuric acid or ofa strong organic sulphonic acid, such as p-toluenesulphonic acid, and ofa suitable solvent, such as of a lower alkanol, for example ethanol, orof an ether, for example dioxane, and thus to arrive at compounds of theformula IA and/or IB, wherein R₃ represents lower alkyl, for examplemethyl or ethyl.

The enol-ethers of the formula IA and/or IB can also be obtained ifstarting substances of the formula II are treated with tri-R₃ -oxoniumsalts of the formula (R₃)₃ O.sup.⊖ A.sup.⊕ (so-called Meerwein salts),as well as di-R₃ Ocarbenium salts of the formula (R₃ O)₂ CH.sup.⊖A.sup.⊕ or di-R₃ halonium salts of the formula (R₃)₂ Hal.sup.⊖ A.sup.⊕ ,wherein A.sup.⊕ denotes the anion of an acid and Hal.sup.⊖ denotes ahalonium ion, especially a bromonium ion. The salt concerned are aboveall tri-lower alkyloxonium salts, as well as di-lower alkoxycarbeniumsalts or di-lower alkylhalonium salts, especially the appropriate saltswith complex acids containing fluorine, such as the appropriatetetrafluoborates, hexafluophosphates, hexfluoantimonates orhexachloroantimonates. Such reagents are, for example, trimethyloxoniumor triethyloxonium hexafluoantimonate, hexachloroantimonate,hexafluophosphate or tetrafluoborate, dimethoxycarbeniumhexafluophosphate or dimethylbromonium hexafluoantimonate. Theseetherifying agents are preferably used in an inert solvent such as anether or a halogenated hydrocarbon, for example diethyl ether,tetrahydrofurane or methylene chloride, or in a mixture thereof, ifnecessary in the presence of a base, such as of an organic base, forexample of a preferably sterically hindered tri-lower alkylamine, forexample N,N-diisopropyl-N-ethyl-amine, and with cooling, at roomtemperature or with slight warming, for example at about -20° C. toabout 50° C., if necessary in a closed vessel and/or in an inert gasatmosphere, for example a nitrogen atmosphere.

The enol-ethers of the formulae IA and/or IB can also be manufactured bytreating starting substances of the formula II with a 3-substituted 1-R₃-triazene compound (that is to say a compound of the formulaSubst.-N═N-NH-R₃), the substituent of the 3-nitrogen atom denoting anorganic radical bonded via a carbon atom, preferably a carbocyclic arylradical, such as an optionally substituted phenyl radical, for examplelower alkylphenyl, such as 4-methyl-phenyl. Such triazene compounds are3-aryl-1-lower alkyl-triazenes, for example3-(4-methylphenyl)-1-methyl-triazene,3-(4-methylphenyl)-1-ethyl-triazene,3-(4-methylphenyl)-1-n-propyltriazene or3-(4-methylphenyl)-1-isopropyl-triazene, and also3-aryl-1-(α-phenyl-lower alkyl)-triazenes, for example1-benzyl-3-(4-methyl-phenyl)-triazene. These reagents are usuallyemployed in the presence of inert solvents, such as optionallyhalogenated hydrocarbons or ethers, for example benzene or solventmixtures, and with cooling, at room temperature and preferably atelevated temperature, for example at about 20° C. to about 100° C., ifnecessary in a closed vessel and/or in an inert gas atmosphere, forexample a nitrogen atmosphere.

In the process according to the invention, and in additional measureswhich may require to be carried out it is possible, if necessary,temporarily to protect, in a manner which is in itself known, freefunctional groups, which do not participate in the reaction, in thestarting substances, or in the compounds obtainable according to theprocess, for example free amino groups by, for example, acylation,tritylation or silylation, free hydroxyl or mercapto groups by, forexample, etherification or esterification, and free carboxyl groups by,for example, esterification, including silylation and in each case toliberate them after the reaction has taken place, if desired,individually or conjointly, in a manner, which is in itself known. Thusit is preferably possible, for example, to protect amino, hydroxyl,carboxyl or phosphono groups in an acyl radical R₁ ^(A) or R₁ ^(b), forexample in the form of acylamino groups, such as those mentioned above,for example 2,2,2-trichloroethoxycarbonylamino,2-bromoethoxycarbonylamino, 4-methoxybenzyloxycarbonylamino,diphenylmethoxycarbonylamino or tert.-butoxycarbonylamino groups, ofarylthioamino or aryl-lower alkylthioamino groups, for example2-nitrophenylthioamino groups, or arylsulphonylamino groups, for example4-methylphenylsulphonylamino groups, or of 1-lower alkoxycarbonyl-2-propylideneamino groups, or, respectively, of acyloxy groups, such asthose mentioned above, for example tert.-butoxycarbonyloxy,2,2,2-trichloroethoxycarbonyloxy or 2-bromoethoxycarbonyloxy groups, or,respectively, of esterified carboxyl groups, such as those mentionedabove, for example diphenylmethoxycarbonyl groups, or, respectively,O,O'-disubstituted phosphono groups, such as those mentioned above, forexample O,O'-di-lower alkylphosphono groups, for exampleO,O'-dimethylphosphono groups and subsequently, optionally afterconversion of the protective group, for example of a2-bromoethoxycarbonyl group into a 2-iodoethoxycarbonyl group, to splitthe protected group in a manner which is in itself known and dependingon the nature of the protective group, for example a2,2,2-trichloroethoxycarbonylamino or 2-iodoethoxycarbonylamino group bytreatment with suitable reducing agents, such as zinc in the presence ofaqueous acetic acid, a diphenylmethoxycarbonylamino ortert.-butoxycarbonylamino group by treatment with formic acid ortrifluoroacetic acid, an arylthioamino or aryl-lower alkylthioaminogroup by treatment with a nucleophilic reagent, such as sulphurous acid,an arylsulphonylamino group by means of electrolytic reduction, a1-lower alkoxycarbonyl-2-propylideneamino group by treatment with anaqueous mineral acid, or a tert.-butoxycarbonyloxy group by treatmentwith formic acid or trifluoroacetic acid, or a2,2,2-trichloroethoxycarbonyloxy group by treatment with a chemicalreducing agent, such as zinc in the presence of aqueous acetic acid, ora diphenylmethoxycarbonyl group by treatment with formic acid ortrifluoroacetic acid or by hydrogenolysis, or an O,O'-disubstitutedphosphono group by treatment with an alkali metal halide, the splittingbeing carried out if desired, for example partially.

In a compound of the formula IA or IB obtainable according to theinvention and possessing a protected, especially esterified, carboxylgroup of the formula -C(═O)-R₂ ^(A), the latter can be converted intothe free carboxyl group in a manner which is in itself known, forexample depending on the nature of the group R₂ ^(A). An esterifiedcarboxyl group, for example a carboxyl group esterified by a lower alkylradical, especially methyl or ethyl, or by a benzyl radical, especiallyin a 2-cephem compound of the formula IB, can be converted into a freecarboxyl group by hydrolysis in a weakly basic medium, for example bytreatment with an aqueous solution of an alkali metal hydroxide orcarbonate or alkaline earth metal hydroxide or carbonate, for examplesodium hydroxide or potassium hydroxide, preferably at a pH value ofabout 9 to 10, and optionally in the presence of a lower alkanol. Acarboxyl group esterified by a suitable 2-halogeno-lower alkyl group orby an arylcarbonylmethyl group can be split, for example, by treatmentwith a chemical reducing agent, such as a metal, for example zinc, or areducing metal salt, such as a chromium-II salt, for example chromium-IIchloride, usually in the presence of a hydrogen donor which is capableof producing nascent hydrogen together with the metal, such as an acid,above all acetic acid also formic acid, or an alcohol, water being addedpreferably, a carboxyl group esterified by an arylcarbonylmethyl groupcan also be split by treatment with a nucleophilic, preferablysaltforming, reagent, such as sodium thiophenolate or sodium iodide, acarboxyl group esterified by a suitable arylmethyl grouping can besplit, for example, by irradiation, preferably with ultraviolet light,for example below 290 mμ, if the arylmethyl group represents, forexample, a benzyl radical which is optionally substituted in the 3-, 4-and/or 5-position, for example by lower alkoxy and/or nitro groups, orwith ultraviolet light of longer wavelengths, for example above 290 mμ,if the arylmethyl group denotes, for example, a benzyl radical which issubstituted by a nitro group in the 2-position, a carboxyl group whichis esterified by a suitably substituted methyl group, such astert.-butyl or diphenylmethyl can be split, for example, by treatmentwith a suitable acid agent, such as formic acid or trifluoroacetic acid,optionally with the addition of a nucleophilic compound, such as phenolor anisole, an activated esterified carboxyl group, and also a carboxylgroup present in the form of an anhydride, can be split by hydrolysisfor example by treatment with an acid or weakly basic aqueous agent,such as hydrochloric acid or aqueous sodium bicarbonate or an aqueouspotassium phosphate buffer of pH about 7 to about 9, and an esterifiedcarboxyl group which can be split hydrogenolytically can be split byhydrogenolysis, for example by treatment with hydrogen in the presenceof a noble metal catalyst, for example a palladium catalyst.

A carboxyl group protected, for example, by silylation or stannylationcan be liberated in the usual manner, for example by treatment withwater or an alcohol.

Resulting compounds of the formula IA or IB can be converted in a mannerwhich is in itself known into other compounds of the formula IA or IB.

In a resulting compound it is possible, for example, to split off anamino protective group R₁ ^(A) or R₁ ^(b), especially an easilyremovable acyl group, in a manner which is in itself known, for examplean α-poly-branched lower alkoxycarbonyl group, such astert.-butoxycarbonyl, by treatment with trifluoroacetic acid, anda2-halogeno-lower alkoxycarbonyl group, such as2,2,2-trichloroethoxycarbonyl or 2-iodoethoxycarbonyl or ahenacyloxycarbonyl group, by treatment with a suitable reducing metal orcorresponding metal compound, for example zinc, or a chromium-IIcompound, such as chromium-II chloride or chromium-II acetate,advantageously in the presence of an agent which together with the metalor the metal compound generates nascent hydrogen, preferably in thepresence of aqueous acetic acid.

It is furthermore possible, in a resulting compound of the formula IA orIB, wherein a carboxyl group of the formula -C(═O)-R₂ preferablyrepresents a carboxyl group which is protected, for example byesterification, including silylation, for example by reaction with asuitable organic halogenosilicon compound or halogeno-tin-IV compound,such as trimethylchlorosilane or tri-n-butyl-tin chloride, to split offan acyl group R₁ ^(a) or R₁ ^(b), wherein optionally present freefunctional groups are optionally protected, by treatment with animide-halide-forming agent, reaction of the resulting imide-halide withan alcohol and splitting of the imino-ether formed, it being possiblefor a protected carboxyl group, for example a carboxyl group protectedby an organic silyl radical, already to be liberated in the course ofthe reaction.

Imide-halide-forming agents in which halogen is bonded to anelectrophilic central atom are above all acid halides, such as acidbromides and especially acid chlorides. The acid halides are above allacid halides of inorganic acids, above all of acids containingphosphorus, such as phosphorus oxyhalides, phosphorus trihalides andespecially phosphorus pentahalides, for example phosphorus oxychloride,phosphorus trichloride and above all phosphorus pentachloride, and alsopyrocatechyl-phosphorus trichloride, as well as acid halides, especiallyacid chlorides, of acids containing sulphur or of carboxylic acids, suchas thionyl chloride, phosgene or oxalyl chloride.

The reaction with one of the imide-halide-forming agents mentioned isusually carried out in the presence of a suitable base, especially of anorganic base, above all of a tertiary amine, for example a tertiaryaliphatic monoamide or diamine, such as a tri-lower alkylamin, forexample trimethylamine, triethylamine or N,N-diisopropyl-N-ethylamine,also a N,N,N',N'-tetra-lower alkyl-lower alkylenediamine, for exampleN,N,N',N'-tetramethyl-1,5-pentylenediamine orN,N,N',N'-tetramethyl-1,6-hexylenediamine, a monocyclic or bicyclicmonoamine or diamine, such as a N-substituted, for example N-loweralkylated, alkyleneamine, azaalkyleneamine or oxaalkyleneamine, forexample N-methyl-piperidine or N-methyl-morpholine, as well as2,3,4,6,7,8-hexahydro-pyrrolo[1,2-a]pyrimidine (diazabicyclo-nonene;DBN), or a tertiary aromatic amine such as a di-lower alkylaniline, forexample N,N-dimethylaniline, or above all a tertiary heterocyclic,monocyclic or bicyclic, base, such as quinoline or isoquinoline,especially pyridine, preferably in the presence of a solvent, such as anoptionally halogenated, for example chlorinated, aliphatic or aromatichydrocarbon, for example methylene chloride. It is possible to useapproximately equimolar amounts of the imide-halide-forming agent and ofthe base; the latter can, however, also be present in more than or lessthan equimolar amount, for example in about 0.2-fold to about 1-foldamount or in, say, up to 10-fold, in particular about 3-fold to 5-fold,excess.

The reaction with the imide-halide-forming agent is preferably carriedout with cooling, for example at temperaturesof about -50° C. to about+10° C., but it is also possible to work at higher temperatures, that isto say, for example, up to about 75° C., if the stability of thestarting substances and of the products permits a higher temperature.

The imide-halide product which is usually further processed withoutisolation, is reacted according to the process with an alcohol,preferably in the presence of one of the abovementioned bases, to givethe imino-ether. Examples of suitable alcohols are aliphatic as well asaraliphatic alcohols, above all optionally substituted, such ashalogenated, for example chlorinated, lower alkanols or lower alkanolspossessing additional hydroxyl groups, for example ethanol, propanol orbutanol but especially methanol, also 2-halogeno-lower alkanols, forexample 2,2,2-trichloroethanol or 2-bromoethanol, and optionallysubstituted phenyl-lower alkanols, such as benzyl alcohol. Usually anexcess, for example up to about 100-fold excess, of the alcohol isemployed and the reaction is preferably carried out with cooling, forexample at temperatures of about -50° C. to about 10° C.

The imino-ether product can advantageously be split without isolation.The splitting of the imino-ether can be achieved by treatment with asuitable hydroxy compound, preferably by means of hydrolysis, and alsoby alcoholysis, and the latter can take place directly following theformation of the imino-ether, if an excess of the alcohol is used.Preferably, water or an alcohol, especially a lower alkanol, for examplemethanol, or an aqueous mixture of an organic solvent, such as analcohol, is used. The reaction is usually carried out in an acid medium,for example at a pH value of about 1 to about 5 which can, if necessary,be obtained by adding a basic agent, such as an aqueous alkali metalhydroxide, for example sodium hydroxide or potassium hydroxide, or anacid, for example a mineral acid, or an organic acid, such ashydrochloric acid, sulphuric acid, phosphoric acid, fluoboric acid,trifluoroacetic acid or p-toluenesulphonic acid.

The three-stage process for splitting off an acyl group, describedabove, is advantageously carried out without isolation of theimide-halide and imino-ether intermediate products, usually in thepresence of an organic solvent which is inert towards the reactants,such as an optionally halogenated hydrocarbon, for example methylenechloride, and/or in an inert gas atmosphere, such as a nitrogenatmosphere.

If the imide-halide intermediate product obtained according to the aboveprocess, instead of being reacted with an alcohol, is reacted with asalt, such as an alkali metal salt, of a carboxylic acid, especially ofa sterically hindered carboxylic acid, a compound of the formula IA orIB, wherein both radicals R₁ ^(a) and R₁ ^(b) represent acyl groups, isobtained.

In a compound of the formula IA or IB, wherein both radicals R₁ ^(a) andR₁ ^(b) represent acyl groups, one of these groups, preferably thesterically less hindered group, can be removed selectively, for exampleby hydrolysis or aminolysis.

In a compound of the formulae IA or IB, wherein R₁ ^(A) and R₁ ^(b)together with the nitrogen atom represent a phthalimido group, thelatter can be converted into the free amino group, for example byhydrazinolysis, that is to say on treatment of such a compound withhydrazine.

Certain acyl radicals R₁ ^(A) of an acylamino grouping in compoundsobtainable according to the invention such as, for example, the5-amino-5-carboxy-valeryl radical, wherein carboxyl is optionallyprotected, for example by esterification, especially by diphenylmethyl,and/or the amino group is optionally protected, for example byacylation, especially by an acyl radical of an organic carboxylic acid,such as halogeno-lower alkanoyl, such as dichloroacetyl, or phthaloyl,can also be split off by treatment with a nitrosylating agent, such asnitrosyl chloride, with a carbocyclic arenediazonium salt, such asbenzenediazonium chloride, or with an agent which releases positivehalogen, such as a N-halogeno-amine or -imide, for exampleN-bromosuccinimide, preferably in a suitable solvent or solvent mixture,such as formic acid, together with a nitro- or cyano-lower alkane, andtreatment of the reaction product with a hydroxylic agent, such as wateror a lower alkanol, for example methanol or, if in the5-amino-5-carboxy-valeryl radical R₁ ^(A) the amino group is substitutedand the carboxyl group is protected, for example by esterification, andR₁ ^(b) preferably represents an acyl radical but can also denotehydrogen, by leaving the substance to stand in an inert solvent, such asdioxane or a halogenated aliphatic hydrocarbon, for example methylenechloride and, if necessary, working up the free or monoacylated aminocompound according to methods which are in themselves known.

A formyl group R₁ ^(A) can also be split off by treatment with an acidagent, for example p-toluenesulphonic acid or hydrochloric acid, aweakly basic agent, for example dilute ammonia, or a decarbonylatingagent, for example tris(triphenylphosphine)-rhodium chloride.

A triarylmethyl group, such as the trityl group R₁ ^(A), can be splitoff, for example by treatment with an acid agent, such as a mineralacid, for example hydrochloric acid.

In a compound of the formula IA or IB, wherein R₁ ^(a) and R₁ ^(b)represent hydrogen, the free amino group can be substituted according tomethods which are in themselves known, above all acylated by treatmentwith acids, such as carboxylic acids, or reactive derivatives thereof.

If a free acid wherein optionally present functional groups, such as anoptionally present amino group, are preferably protected, is employedfor the acylation, suitable condensation agents are usually employed,such as carbodiimides, for example N,N'-diethyl-, N,N'-dipropyl-,N,N'-diisopropyl-, N,N'-dicyclohexyl- orN-ethyl-N'-3-dimethylaminopropyl-carbodiimide, suitable carbonylcompounds, for example carbonyl diimidazole, or isoxazolinium salts, forexample N-ethyl-5-phenyl-isoxazolinium-3'-sulfonate andN-tert.-butyl5-methyl-isoxazolinium perchlorate, or a suitable acylaminocompound, for example 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline.

The condensation reaction is preferably carried out in one of theanhydrous reaction media mentioned later, for example in methylenechloride, dimethylformamide or acetonitrile.

An amide-forming functional derivative of an acid, wherein optionallypresent groups, such as an optionally present amino group, arepreferably protected, is above all an anhydride of such an acid,including, and preferably, a mixed anhydride. Mixed anhydrides are, forexample, those with inorganic acids, especially with hydrogen halideacids, that is to say the corresponding acid halides, for example acidchlorides or acid bromides, and also with hydrazoic acid, that is to saythe corresponding acid azides, with an acid containing phosphorus, forexample phosphoric acid or phosphorous acid, with an acid containingsulphur, for example sulphuric acid, or with hydrocyanic acid. Furthermixed anhydrides are, for example, those with organic acids, such asorganic carboxylic acids, such as with lower alkanecarboxylic acidswhich are optionally substituted, for example by halogen, such asfluorine or chlorine, for example pivalic acid or trichloroacetic acid,or with half-esters, especially lower alkyl half-esters, of carbonicacid, such as the ethyl half-ester or isobutyl half-ester of carbonicacid, or with organic, especially aliphatic or aromatic, sulphonicacids, for example p-toluenesulphonic acid.

It is furthermore possible to use, as acylating agents, inneranhydrides, such as ketenes, for example diketene, isocyanates, (that isto say inner anhydrides of carbamic acid compounds) or inner anhydridesof carboxylic acid compounds having carboxyl-substituted hydroxyl oramino groups, such as mandelic acid O-carboxanhydride or the anhydrideof 1-N-carboxyamino-cyclohexanecarboxylic acid.

Further acid derivatives suitable for reaction with the free amino groupare activated esters, wherein optionally present functional groups areusually protected, such as esters with vinylogous alcohols, (that is tosay enols), such as vinylogous lower alkanols, or aryl esters, such asphenyl esters which are preferably substituted, for example by nitro orhalogen, such as chlorine, for example pentachlorophenyl, 4-nitrophenylor 2,4-dinitrophenyl esters, hetero-aromatic esters, such asbenztriazole esters, or diacylimino esters, such as succinylimino estersor phthalylimino esters.

Further acylation derivatives are, for example, substituted formiminoderivatives, such as substituted N,N-dimethylchloroformimino derivativesof acids, or N-substituted N,N-diacylamines, such as a N,N-diacylatedaniline.

The acylation with an acid derivative, such as an anhydride, andespecially with an acid halide, can be carried out in the presence of anacid-binding agent, for example of an organic base, such as an organicamine, for example a tertiary amine, such as tri-lower alkylamine, forexample triethylamine, N,N-di-lower alkylaniline, for exampleN,N-dimethylaniline, or a base of the pyridine type, for examplepyridine, an inorganic base, for example an alkali metal hydroxide,carbonate or bicarbonate or an alkaline earth metal hydroxide, carbonateor bicarbonate, for example sodium hydroxide, carbonate or bicarbonate,potassium hydroxide, carbonate or bicarbonate or calcium hydroxide,carbonate or bicarbonate, or of an oxirane, for example a lower1,2-alkylene oxide, such as ethylene oxide or propylene oxide.

The above acylation can be carried out in an aqueous or, preferably,non-aqueous solvent or solvent mixture, for example in a carboxylic acidamide, such as a N,N-di-lower alkylamide, for example dimethylformamide,a halogenated hydrocarbon, for example methylene chloride, carbontetrachloride or chlorobenzene, a ketone, for example acetone, an ester,for example ethyl acetate, or a nitrile, for example acetonitrile, ormixtures thereof, and, if necessary, at lowered, or elevated temperatureand/or in an inert gas atmosphere, for example a nitrogen atmosphere.

In the above N-acylation reactions it is possible to start fromcompounds of the formulae IA or IB, wherein R₃ is lower alkyl or anoptionally substituted α-phenyl-lower alkyl group, for example a benzylor diphenylmethyl group, and R₂ has the above meaning, and compoundshaving free carboxyl groups of the formula --C(═O)--R₂, wherein R₂represents hydroxyl, can also be used in the form of salts, for exampleammonium salts, such as with triethylamine, or in the form of a compoundwith a carboxyl group protected by reaction with a suitable organicphosphorus halide compound, such as with a lower alkyl- or loweralkoxy-phosphorus dihalide, such as methyl-phosphorus dichloride,ethyl-phosphorus dibromide or methoxyphosphorus dichloride; in theresulting acylation product the protected carboxyl group can beliberated in a manner which is in itself known, for example as describedabove, including by hydrolysis or alcoholysis.

An acyl group can also be introduced by acylating a compound of theformula IA or IB, wherein R₁ ^(a) and R₁ ^(b) together represent anylidene radical, (which can also be introduced subsequently, for exampleby treating a compound wherein R₁ ^(a) and R₁ ^(b) represent hydrogen,with an aldehyde, such as an aliphatic, aromatic or araliphaticaldehyde), for example according to the methods indicated above, and theacylation product can be hydrolysed, preferably in a neutral or weaklyacid medium.

An acyl group can also be introduced stepwise. Thus, for example, it ispossible to introduce into a compound of the formula IA or IB, having afree amino group, a halogenolower alkanoyl group, for example abromoacetyl group, or, for example by treatment with a carbonic aciddihalide, such as phosgene, a halogenocarbonyl group, for example achlorocarbonyl group, and to react a N-(halogeno-lower alkanoyl)-aminocompound or N-(halogenocarbonyl)-amino compound thus obtainable withsuitable exchange reagents, such as basic compounds, for exampletetrazole, thio compounds, for example 2-mercapto-1-methyl-imidazole, ormetal salts, for example sodium azide, or alcohols, such as loweralkanols, for example tert.-butanol and thus to obtain substitutedN-lower alkanoyl-amino or N-hydroxycarbonylamino compounds.

In both reactants, free functional groups can temporarily be protectedduring the acylation reaction, in a manner which is in itself known andbe liberated, after the acylation, by means of methods which are inthemselves known, for example as described above.

The acylation can also be effected by replacement of an already existingacyl group by another, preferably sterically hindered, acyl group, forexample according to the process described above, by manufacturing theimide-halide compound, treating this with a salt of an acid andsplitting off hydrolytically one of the acyl groups present in theproduct thus obtainable, usually the sterically less hindered acylgroup.

It is furthermore possible, for example, to react a compound of theformula IA or IB, wherein R₁ ^(a) represents a glycyl group which ispreferably substituted in the α-position, such as phenylglycyl, and R₁^(b) represents hydrogen, with an aldehyde, for example formaldehyde, ora ketone, such as a lower alkanone, for example acetone, and thus toarrive at compounds of the formula IA or IB, wherein R₁ ^(A) and R₁ ^(b)together with the nitrogen atom represent a 5-oxo-1,3-diaza-cyclopentylradical which is preferably substituted in the 4-position and isoptionally substituted in the 2-position.

In a compound of the formula IA or IB, wherein R₁ ^(a) and R₁ ^(b)represent hydrogen, the free amino group can also be protected byintroducing a triarylmethyl group, for example by treatment with areactive ester of a triarylmethanol, such as trityl chloride, preferablyin the presence of a basic agent, such as pyridine.

An amino group can also be protected by introducing a silyl and stannylgroup. Such groups are introduced in a manner which is in itself known,for example by treatment with a suitable silylating agent, such as witha dihalogenodi-lower alkylsilane, lower alkoxy-loweralkyl-dihalogenosilane or tri-lower alkyl-silyl halide, for exampledichlorodimethylsilane, methoxy-methyl-dichloro-silane, trimethylsilylchloride or dimethyl-tert.-butyl-silyl chloride, such silyl halidecompounds preferably being used in the presence of a base, for examplepyridine, or by treatment with an optionally N-mono-lower alkylated,N,N-di-lower alkylated, N-tri-lower alkylsilylated or N-loweralkyl-N-tri-lower alkyl-silylated N-(tri-lower alkylsilyl)-amine (see,for example, British Pat. No. 1,073,530), or with a silylated carboxylicacid amide, such as a bis-tri-lower alkylsilylacetamide, for examplebis-trimethylsilyl-acetamide or trifluorosilylacetamide, or by treatmentwith a suitable stannylating agent, such as a bis-(tri-lower alkyl-tin)oxide, for example bis-(tri-n-butyl-tin) oxide, a tri-lower alkyl-tinhydroxide, for example triethyl-tin hydroxide, a tri-lower alkyl-loweralkoxy-tin compound, tetra-lower alkoxy-tin compound or tetra-loweralkyl-tin compound, or with a tri-lower alkyl-tin halide, for exampletri-n-butyl-tin chloride (see, for example, Netherlands PublishedSpecification 67/11,107).

In a compound of the formula IA or IB, obtainable according to theprocess, which contains a free carboxyl group of the formula--C(═O)--R₂, such a group can be converted into a protected carboxylgroup in a manner which is in itself known. Thus esters are obtained,for example, by treatment with a suitable diazo compound, such as adiazolower alkane, for example diazomethane or diazobutane, or aphenyl-diazo-lower alkane, for example diphenyldiazomethane, ifnecessary in the presence of a Lewis acid, such as, for example, borontrifluoride, or by reaction with an alcohol suitable for theesterification reaction, in the presence of an esterifying agent, suchas a carbodiimide, for example dicyclohexylcarbodiimide, as well ascarbonyldiimidazole, and also with a N,N'-disubstituted O- orS-substituted isourea or isothiourea, wherein a O-substituent andS-substituent are, for example, lower alkyl, especially tert.-butyl,phenyllower alkyl or cycloalkyl, and N-substituents or N'-substituentsare, for example, lower alkyl, especially isopropyl, cycloalkyl orphenyl, or according to any other known and suitable esterificationprocess, such as reaction of a salt of the acid with a reactive ester ofan alcohol and of a strong inorganic acid, or with a strong organicsulphonic acid. Furthermore, acid halides, such as acid chlorides(manufactured, for example, by treatment with oxalyl chloride),activated esters (formed, for example, with N-hydroxy-nitrogencompounds, such as N-hydroxy-succinimide), or mixed anhydrides(obtained, for example, with halogenoformic acid lower alkyl esters,such as chloroformic acid ethyl ester or chloroformic acid isobutylester, or with halogenoacetic acid halides, such as trichloroacetic acidchloride) can be converted into an esterified carboxyl group by reactionwith alcohols, optionally in the presence of a base, such as pyridine.

In a resulting compound having an esterified grouping of the formula--C(═O)--R₂, this grouping can be converted into a different esterifiedcarboxyl group of this formula, for example 2-chloroethoxycarbonyl or2-bromoethoxycarbonyl can be converted into 2-iodoethoxycarbonyl bytreatment with an iodine salt, such as sodium iodide, in the presence ofa suitable solvent, such as acetone.

Mixed anhydrides can be manufactured by reacting a compound of theformula IA or IB, having a free carboxyl group of the formula--C(═O)--R₂, preferably a salt, especially an alkali metal salt, forexample a sodium salt, or ammonium salt, for example triethylammoniumsalt, thereof, with a reactive derivative, such as a halide, for examplethe chloride, of an acid, for example a halogenoformic acid lower alkylester or a lower alkanecarboxylic acid chloride.

In a compound obtainable according to the process, having a freecarboxyl group of the formula --C(═O)--R₂, such a group can also beconverted into an optionally substituted carbamoyl or hydrazinocarbonylgroup, for which preferably reactive functionally modified derivatives,such as the above-mentioned acid halides, and generally esters,including also the abovementioned activated esters, or mixed anhydridesof the appropriate acid are reacted with ammonia or amines, includinghydroxylamine, or hydrazines.

A carboxyl group protected by an organic silyl or stannyl group can beformed in a manner which is in itself known, for example by treatingcompounds of the formulae IA or IB, wherein R₂ represents hydroxyl, orsalts thereof, such as alkali metal salts thereof, for example sodiumsalts thereof, with a suitable silylating or stannylating agent, such asone of the abovementioned silylating or stannylating agents; see, forexample, British Pat. No. 1,073,530 or Netherlands PublishedSpecification No. 67/17,107.

It is furthermore possible to liberate modified functional substituentsin groups R₁ ^(A), R₁ ^(b) and/or R₂, such as substituted amino groups,acylated hydroxyl groups, esterified carboxyl groups orO,O'-disubstituted phosphono groups, according to methods which are inthemselves known, for example those described above, or functionally tomodify free functional substituents in groups R₁ ^(A), R₁ ^(b) and/orR₂, such as free amino, hydroxyl, carboxyl or phosphono groups,according to processes which are in themselves known, for exampleacylation or esterification or substitution. Thus, for example, an aminogroup can be converted into a sulphoamino group by treatment withsulphur trioxide, preferably in the form of a complex with an organicbase, such as a tri-lower alkylamine, for example triethylamine.Furthermore, the reaction mixture obtained by reaction of an acidaddition salt of a 4-guanylsemicarbazide with sodium nitrite can bereacted with a compound of the formula IA or IB, wherein, for example,the amino protective group R₁ ^(A) represents an optionally substitutedglycyl group, and the amino group can thus be converted into a3-guanylureido group. Further, compounds with aliphatically bondedhalogen, for example with an optionally substituted α-bromoacetylgrouping, can be reacted with esters of phosphorus acid, such astri-lower alkyl-phosphite compounds, and corresponding phosphonocompounds can thus be obtained.

Resulting cephem compounds of the formula IA and IB can be convertedinto 1-oxides of the corresponding 3-cephem compounds of the formula IAby oxidation with suitable oxidising agents, such as those describedbelow. Resulting 1-oxides of 3-cephem compounds of the formula IA can bereduced to the corresponding 3-cephem compounds of the formula IA byreduction with suitable reducing agents such as, for example, thosedescribed below. In these reactions it is necessary to ensure that, ifnecessary, free functional groups are protected and are subsequentlyagain liberated, if desired.

Cephem compounds obtained can be isomerised. Thus, resulting 2-cephemcompounds of the formula IB, or resulting mixtures of 2-cephem and3-cephem compounds, can be converted into the corresponding 3-cephemcompounds of the formula IA by isomerising a 2-cephem compound of theformula IB, or a mixture consisting of a 2-cephem and 3-cephem compound,wherein free functional groups can, if appropriate, be protectedtemporarily, for example as indicated. In this reaction it is possibleto use, for example, 2-cephem compounds of the formula IB wherein thegroup of the formula --C(═O)--R₂ represents a free or protected carboxylgroup, it also being possible to form a protected carboxyl group duringthe reaction.

Thus it is possible to isomerise a 2-cephem compound of the formula IBby treating it with a basic agent and isolating the corresponding3-cephem compound of the formula IA from an equilibrium mixture of the2- and 3-cephem compounds which may be obtained.

Examples of suitable isomerising agents are organic nitrogen-containingbases, such as tertiary heterocyclic bases of aromatic character, andabove all tertiary aliphatic, azacycloaliphatic or araliphatic bases,such as N,N,N-tri-lower alkylamines, for example N,N,N-trimethylamine,N,N-dimethyl-N-ethylamine, N,N,N-triethylamine orN,N-diisopropyl-N-ethylamine, N-lower alkyl-azacycloalkanes, for exampleN-methyl-piperidine, or N-phenyl-lower alkyl-N,N-di-lower alkyl-amines,for example N-benzyl-N,N-dimethylamine, as well as mixtures thereof,such as the mixture of a base of the pyridine type, for examplepyridine, and a N,N,N-trilower alkylamine, for example pyridine andtriethylamine. Furthermore it is also possible to use inorganic ororganic salts of bases, especially of medium strength to strong bases,with weak acids, such as alkali metal salts or ammonium salts of loweralkanecarboxylic acids, for example sodium acetate, triethylammoniumacetate or N-methyl-piperidine acetate, as well as other analogous basesor mixtures of such basic agents.

The above isomerisation with basic agents can be carried out forexample, in the presence of a derivative of a carboxylic acid which issuitable for forming a mixed anhydride, such as a carboxylic acidanhydride or carboxylic acid halide, for example with pyridine in thepresence of acetic anhydide. This reaction is preferably carried out inan anhydrous medium, in the presence or absence of a solvent, such as anoptionally halogenated, for example chlorinated, aliphatic,cycloaliphatic or aromatic hydrocarbon, or of a solvent mixture, itbeing possible for bases used as reactants and liquid under the reactionconditions at the same time also to serve as solvents, if necessary withcooling or heating, preferably in a temperature range of about -30° C.to about +100° C., in an inert gas atmosphere, for example a nitrogenatmosphere, and/or in a closed vessel.

The 3-cephem compounds of the formula IA, thus obtainable, can beseparated from 2-cephem compounds of the formula IB which may still bepresent, in a manner which is in itself known, for example by adsorptionand/or crystallisation.

The isomerisation of 2-cephem compounds of the formula IB can also becarried out by oxidising these in the 1-position, if desired separatingan isomer mixture of the 1-oxides of 3-cephem compounds of the formulaIA which may be obtained, and reducing the 1-oxides of the corresponding3-cephem compounds of the formula IA, thus obtainable.

Suitable oxidising agents for the oxidation of 2-cephem compounds in the1-position are inorganic per-acids which have a reduction potential ofat least +1.5 volt and which consist of non-metallic elements, organicper-acids or mixtures of hydrogen peroxide and acids, especially organiccarboxylic acids, having a dissociation constant of at least 10⁻⁵.Suitable inorganic per-acids are periodic acid and persulphuric acid.Organic per-acids are appropriate percarboxylic acids and persulphuricacids which can be added as such or can be formed in situ by the use ofat least one equivalent of hydrogen peroxide and of a carboxylic acid.It is desirable to use a large excess of the carboxylic acid if, forexample, acetic acid is used as the solvent. Suitable per-acids are, forexample, performic acid, peracetic acid, pertrifluoroacetic acid,permaleic acid, perbenzoic acid, monoperphthalic acid orp-toluenepersulphonic acid.

The oxidation can also be carried out using hydrogen peroxide andcatalytic amounts of an acid having a dissociation constant of at least10⁻⁵, it being possible to employ low concentrations, for example 1-2%or less, but also larger amounts, of the acid. The activity of themixture above all depends on the strength of the acid. Examples ofsuitable mixtures are those of hydrogen peroxide with acetic acid,perchloric acid or trifluoroacetic acid.

The above oxidation can be carried out in the presence of suitablecatalysts. Thus, for example, the oxidation with percarboxylic acids canbe catalysed by the presence of an acid having a dissociation constantof at least 10⁻⁵, its activity depending on its strength. Acids suitableas catalysts are, for example, acetic acid, perchloric acid, andtrifluoroacetic acid. Usually, at least equimolar amounts of theoxidizing agent, and preferably a small excess of about 10% to about20%, are used. The oxidation is carried out under mild conditions, forexample at temperatures of about -50° C. to about +100° C., preferaly ofabout -10° C. to about +40° C.

The oxidation of 2-cephem compounds to the 2-oxides of the corresponding3-cephem compounds can also be carried out by treatment with ozone, aswell as with organic hypohalite compounds, such as lower alkylhypochlorites, for example tert.-butylhypochlorite, which are used inthe presence of inert solvents, such as optionally halogenatedhydrocarbons, for example methylene chloride, and at temperatures ofabout -10° C. to about +30° C., with periodate compounds, such as alkalimetal periodates, for example potassium periodate, which are preferablyused in an aqueous medium at a pH value of about 6 and at temperaturesof about -10° C. to about +30° C., with iodobenzene dichloride, which isused in an aqueous medium, preferably in the presence of an organicbase, for example pyridine, and with cooling, for example attemperatures of about -20° C. to about 0°, or with any other oxidisingagent which is suitable for conversion of a thio group into a sulphoxidegrouping.

In the 1-oxides of 3-cephem compounds of the formula IA, thusobtainable, especially in those compounds in which R₁ ^(a), R₁ ^(b) andR₂ have the abovementioned preferred meanings, the groups R₁ ^(a), R₁^(b) and/or R₂ can, within the defined framework, be converted into oneanother, split off or introduced. A mixture of isomeric α- andβ-1-oxides can be separated, for example chromatographically.

The reduction of the 1-oxides of 3-cephem compounds of the formula IAcan be carried out in a manner which is in itself known, by treatmentwith a reducing agent, if necessary in the presence of an activatingagent. Possible reducing agents are: catalytically activated hydrogen,using noble metal catalysts which contain palladium, platinum or rhodiumand which are optionally employed together with a suitable carrier, suchas charcoal or barium sulphate; reducing tin, iron, copper or manganesecations, which are used in the form of appropriate compounds orcomplexes of inorganic or organic nature, for example as tin-IIchloride, fluoride, acetate or formate, iron-II chloride, sulphate,oxalate or succinate, copper-I chloride, benzoate or oxide, ormanganese-II chloride, sulphate, acetate or oxide, or as complexes, forexample with ethylenediamine-tetraacetic acid or nitrilotriacetic acid;reducing dithionite, iodide or ferrocyanide anions which are used in theform of appropriate inorganic or organic salts, such as alkali metalsalts, for example sodium dithionite or potassium dithionite, sodiumiodide or potassium iodide, or sodium ferrocyanide or potassiumferrocyanide, or in the form of the corresponding acids, such ahydriodic acid; reducing trivalent inorganic or organic phosphoruscompounds, such a phosphines, and also esters, amides and halides ofphosphinous, phosphonous or phosphorous acids, as well asphosphorus-sulphur compounds corresponding to these phosphorus-oxygencompounds, in which compounds organic radicals above all representaliphatic, aromatic or araliphatic radicals, for example optionallysubstituted lower alkyl, phenyl or phenyl-lower alkyl groups, such as,for example, triphenylphosphine, tri-n-butylphosphine,diphenylphosphinous acid methyl ester, diphenylchlorophosphine,phenyldichlorophosphine, benzenephosphonous acid dimethyl ester,butanephosphonous acid methyl ester, phosphorous acid triphenyl ester,phosphorous acid trimethyl ester, phosphorus trichloride, phosphorustribromide and the like; reducing halogenosilane compounds which possessat least one hydrogen atom bonded to the silicon atom and which, inaddition to halogen, such as chlorine, bromine or iodine, can alsopossess organic radicals, such as aliphatic or aromatic groups, forexample optionally substituted lower alkyl or phenyl groups, such aschlorosilane, bromosilane, dichlorosilane or trichlorosilane,dibromosilane or tribromosilane, diphenylchlorosilane,dimethylchlorosilane and the like; reducing quaternarychloromethylene-iminium salts, especially chlorides or bromides, whereinthe iminium group in substituted by a bivalent or two monovalent organicradicals, such as optionally substituted lower alkylene or lower alkylgroups, such as N-chloromethylene-N,N-diethyliminium chloride orN-chloromethylene-pyrrolidinium chloride; and the complex metalhydrides, such as sodium borohydride, in the presence of suitableactivating agents, such as cobalt-II chloride, as well as boranedichloride.

As activating agents which are used together with those of theabovementioned reducing agents which do not themselves possess Lewisacid properties, that is to say which above all are employed togetherwith the dithionite, iodide or ferrocyanide reducing agents and thetrivalent phosphorus reducing agents which do not contain halogen, or inthe catalytic reduction, there should especially be mentioned organiccarboxylic acid halides and sulphonic acid halides, also sulphurhalides, phosphorus halides or silicon halides having the same or agreater second order hydrolysis constant than benzoyl chloride, forexample phosgene, oxalyl chloride, acetic acid chloride or acetic acidbromide, or chloroacetic acid chloride, pivalic acid chloride,4-methoxybenzoic acid chloride, 4-cyanobenzoic acid chloride,p-toluenesulphonic acid chloride, methanesulphonic acid chloride,thionyl chloride, phosphorus oxychloride, phosphorus trichloride,phosphorus tribromide, phenyldichlorophosphine, benzenephosphonous aciddichloride, dimethylchlorosilane or trichlorosilane and also suitableacid anhydrides such as trifluoroacetic acid anhydride, or cyclicsultones, such as ethanesultone, 1,3-propanesultone, 1,4-butanesultoneor 1,3-hexanesultone.

The reduction is preferably carried out in the presence of solvents ormixtures thereof, the choice of which is above all determined by thesolubility of the starting substances and the choice of the reducingagent, such as, for example, lower alkanecarboxylic acids or estersthereof, such as acetic acid and ethyl acetate, in the case of thecatalytic reduction and, for example, optionally substituted, such ashalogenated or nitrated, aliphatic, cycloaliphatic, aromatic oraraliphatic hydrocarbons, for example benzene, methylene chloride,chloroform or nitromethane, suitable acid derivatives, such as loweralkanecarboxylic acid esters or nitriles, for example ethyl acetate oracetonitrile, or amides of inorganic or organic acids, for exampledimethylformamide, dimethylacetamide or hexamethylphosphoramide, ethers,for example diethyl ether, tetrahydrofurane or dioxane, ketones, forexample acetone, or sulphones, especially aliphatic sulphones, forexample dimethylsulphone or tetramethylenesulphone, and the like,together with the chemical reducing agents, these solvents preferablynot containing any water. The reaction is usually carried out attemperatures of about -20° C. to about 100° C., it being possible tocarry out the reaction at lower temperatures if very reactive activationagents are used.

In the 3-cephem compounds of the formula IA, thus obtainable, R₁ ^(a),R₁ ^(b) and/or R₂ can be converted into other groups R₁ ^(a), R₁ ^(b) orR₂ as described above.

Salts of compounds of the formula IA and IB can be manufactured in amanner which is in itself known. Thus, salts of such compounds whichpossess acid groups can be formed, for example, by treatment with metalcompounds, such as alkali metal salts, of suitable carboxylic acids, forexample the sodium salt of α-ethyl-caproic acid, or with ammonia or asuitable organic amine, preferably using stoichiometric amounts or onlya small excess of salt-forming agent. Acid addition salts of compoundsof the formulae IA and IB having basic groupings are obtained in thecustomary manner, for example by treatment with an acid or with asuitable anion exchange reagent. Inner salts of compounds of theformulae IA and IB which contain a salt-forming amino group and a freecarboxyl group can be formed, for example, by neutralising salts, suchas acid addition salts, to the isoelectric point, for example with weakbases, or by treatment with liquid ion exchangers. Salts of 1-oxides ofcompounds of the formula IA having salt-forming groups can bemanufactured analogously.

Salts can be converted into the free compounds in the customary manner,metal salts and ammonium salts, for example, by treatment with suitableacids, and acid addition salts, for example, by treatment with asuitable basic agent.

Resulting mixtures of isomers can be separated into the individualisomers according to methods which are in themselves known, mixtures ofdiastereomeric isomers, for example, by fractional crystallisation,adsorption chromatography (column chromatography or thin layerchromatography) or other suitable separation processes. Resultingracemates can be separated into the antipodes in the usual manner, ifappropriate after introducing suitable salt-forming groupings, forexample by forming a mixture of diastereomeric salts with opticallyactive salt-forming agents, separating the mixture into thediastereomeric salts and converting the separated salts into the freecompounds, or by fractional crystallisation from optically activesolvents.

The process also encompasses those embodiments according to whichcompounds arising as intermediate products are used as startingsubstances and the remaining process steps are carried out with these,or the process is stopped at any stage; furthermore, starting substancescan be used in the form of derivatives or be formed during the reaction.

Preferably, these starting substances are used, and the reactionconditions are so chosen, that the compounds initially mentioned asbeing particularly preferred are obtained.

In the starting compounds of the formula II, the group Y which isremoved is preferably a --SO₂ --R₅ group, wherein R₅ has the indicatedmeaning, but especially the indicated preferred meaning.

The process according to the invention is distinguished, relative topreviously known processes, by the fact that it starts from inexpensive,easily accessible starting materials, such as, in particular, the1-oxides of the fermentatively preparable penicillins G or V and of6-aminopenicillanic acid, of which the reactive groups can be protectedin any known manner and can easily be liberated again after thereaction, and that the manufacture of the intermediate products requiredaccording to the invention takes place with high yields.

The starting materials of the formula II used according to the inventioncan be manufactured, for example, in accordance with the followingreaction scheme: ##STR8##

Starting compounds of the formula III are known or can be preparedaccording to known processes.

Compounds of the fomrula IVa are also known or can be prepared accordingto Netherlands Patent Specification 72/08,671.

The new compounds of the formulae IVb, IVc, Va, Vb, Vc, VIa, VIb, VIc,IIa, IIb and IIc, in which R₁ ^(a), R₁ ^(b), R₂ ^(A) and Y have themeaning mentioned under formula II, and processes for their manufacture,are also a subject of the present invention.

Compounds of the formula IVb can be obtained from compounds of theformula III by reaction with a sulphinic acid of the formula HSO₂ --R₅or a sulphonyl cyanide of the formula N.tbd.C--SO₂ --R₅. Compounds ofthe formula IVc can be obtained from compounds of the formula III byreaction with a thiosulphonic acid of the formula H--S--SO₂ --R₅. Thereaction is carried out in an inert solvent or solvent mixture, forexample an optionally halogenated, such as chlorinated, aliphatic,cycloaliphatic or aromatic hydrocarbon, such as pentane, hexane,cyclohexane, benzene, toluene, methylene chloride, chloroform orchlorobenzene, an aliphatic, cycloaliphatic or aromatic alcohol, such asa lower alkanol, for example methanol, ethanol, cyclohexanol or phenol,a polyhydroxy compounds, for example a polyhydroxyalkane, such as adihydroxy-lower alkane, for example ethylene glycol or propylene glycol,a lower ketone, such as acetone or methyl ethyl ketone, an ether-likesolvent, such as diethyl ether, dioxane or tetrahydrofurane, a lowercarboxylic acid amide, such as dimethylformamide or dimethylacetamide, alower dialkyl sulphoxide, such as dimethylsulphoxide and the like, ormixtures thereof.

The reaction is carried out at room temperature or preferably atelevated temperature, for example at the boiling point of the solventemployed, if desired in an inert gas atmosphere, such as a nitrogenatmosphere.

The reaction with the sulphonyl cyanide of the formula N.tbd.C--SO₂ --R₅is accelerated by addition of compounds which provide halogen anions.Examples of suitable compounds which provide halogen anions arequaternary ammonium halides, especially chlorides and bromides, such astetra-lower alkylammonium halides optionally substituted at the loweralkyl groups, for example by aryl, such as phenyl, such astetraethylammonium chloride or bromide or benzyltriethylammoniumchloride or bromide. The compounds which provide halogen anions areadded in amounts of about 1 to about 50 mol percent, preferably of about2 to about 5 mol percent.

Compounds of the formula IVb and IVc can also be obtained by reacting acompound of the formula IVa with a heavy metal sulphinate of the formulaM^(n+) (⁻ SO₂ --R₅)_(n) or with a heavy metal thiosulphonate of theformula M^(n+) (⁻ S--SO₂ --R₅)_(n), wherein M represents a heavy metalcation and n denotes the valency of this cation. Suitable heavy metalsulphinates or heavy metal thiosulphonates are in particular those whichhave a higher solubility product in the reaction medium used than theheavy metal compounds of the formula M^(n+) (--S--R₄)_(n) which areproduced during the reaction. Suitable heavy metal cations M^(n+) are inparticular those which form particularly sparingly soluble sulphides.These include, for example, the monovalent or divalent cations ofcopper, mercury, silver and tin, copper⁺⁺ and silver+ cations beingpreferred.

The heavy metal sulphinate or heavy metal thiosulphonate can either beemployed as such or be formed in situ during the reaction, for examplefrom a sulphinic acid of the formula HSO₂ --R₅ or a thiosulphonic acidof the formula H--S--SO₂ --R₅, or a soluble salt thereof, for example analkali metal salt, such as a sodium salt, and a heavy metal salt ofwhich the solubility product is higher than that of the heavy metalsulphinate or heavy metal thiosulphonate produced, for example a heavymetal nitrate, acetate or sulphate, for example silver nitrate,mercury-II diacetate or copper-II sulphate, or a soluble chloride, suchas tin-II chloride dihydrate.

The reaction of a compound of the formula IVa with the heavy metalsulphinate of the formula M^(n+) (⁻ SO₂ --R₅)_(n) or the heavy metalthiosulphonate of the formula M^(n+) (⁻ S--SO₂ --R₅)_(n) can be carriedout in an inert organic solvent, in water or in a solvent mixtureconsisting of water and a water-miscible solvent. Suitable inert organicsolvents are, for example, aliphatic, cycloaliphatic or aromatichydrocarbons, such as pentane, hexane, cyclohexane, benzene, toluene orxylene, or aliphatic, cycloaliphatic or aromatic alcohols, such as loweralkanols, for example methanol, ethanol, cyclohexanol or phenol,polyhydroxy compounds, such as polyhydroxyalkanes, for exampledihydroxy-lower alkanes, such as ethylene glycol or propylene glycol,carboxylic acid esters, for example lower carboxylic acid lower alkylesters, such as ethyl acetate, lower ketones, such as acetone or methylethyl ketone, ether-like solvents, such as dioxane or tetrahydrofuraneor polyethers, such as dimethoxyethane, lower carboxylic acid amides,such as dimethylformamide, lower alkyl nitriles, such as acetonitrile,or lower sulphoxides, such as dimethylsulphoxide. In water, orespecially in mixtures of water and one of the solvents mentioned,including in emulsions, the reaction usually takes place substantiallymore rapidly than in the organic solvents alone.

The reaction temperature is usually about room temperature but can belowered to slow down the reaction or raised, say up to the boiling pointof the solvent employed, to accelerate the reaction, it being possibleto carry out the reaction under normal or elevated pressure.

In a resulting compound of the formula IV, a group R₁ ^(a), R₁ ^(b) orR₂ ^(A) can be converted into another group R₁ ^(a), R₁ ^(b) or R₂ ^(A),for which purpose it is possible to use analogous reactions to thoseindicated for the conversion of these groups in the case of compounds ofthe formula IA or IB.

In stage 2 and 3 or 2a, a compound of the formula IV can be convertedinto a compound of the formula VI by oxidative degradation of themethylene group to an oxo group.

The oxidative splitting off of the methylene group in compounds of theformula IV to form an oxo group can be carried out by forming an ozonidecompound of the formula V by treatment with ozone. Herein, ozone isusually employed in the presence of a solvent, such as an alcohol, forexample a lower alkanol, such as methanol or ethanol, a ketone, forexample a lower alkanone, such as acetoe, an optionally halogenatedaliphatic, cycloaliphatic or aromatic hydrocarbon, for example ahalogeno-lower alkene, such as methylene chloride or carbontetrachloride, or a solvent mixture, including an aqueous mixture, andwith cooling or slight warming, for example at temperatures of about-90° C. to about +40° C.

An ozonide of the formula Va obtained as an intermediate product can,optionally without isolation, be converted into a compound of theformula Vb or Vc by reaction with a heavy metal sulphinate of theformula M^(n+) (⁻ SO--R₅)_(n) or a heavy metal thiosulphonate of theformula M^(n+) (⁻ S--SO₂ --R₅)_(n), analogously to the conversion ofcompounds of the formula IVa to compounds of the formula IVb or IVc.

An ozonide of the formula V can be split by reduction in stage 3, togive a compound of the formula VI, for which it is possible to usecatalytically activated hydrogen, for example hydrogen in the presenceof a heavy metal hydrogenation catalyst, such as nickel catalyst or apalladium catalyst, preferably on a suitable carrier, such as calciumcarbonate or charcoal, or chemical reducing agents, such as reducingheavy metals, including heavy metal alloys or amalgams, for examplezinc, in the presence of a hydrogen donor, such as an acid, for exampleacetic acid, or an alcohol, for example a lower alkanol, reducinginorganic salts, such as alkali metal iodides, for example sodiumiodide, in the presence of a hydrogen donor, such as an acid, forexample acetic acid, a reducing sulphide compound such as a di-loweralkylsulphide, for example dimethylsulphide, a reducing organicphosphorus compound, such as a phosphine, which can optionally containsubstituted aliphatic or aromatic hydrocarbon radicals as substituents,such as tri-lower alkylphosphines, for examle tri-n-butylphosphine, ortriarylphosphines, for example triphenylphosphine, also phosphites whichcontain optionally substituted aliphatic hydrocarbon radicals assubstituents, such as tri-lower alkylphosphites, usually in the form ofcorresponding alcohol adduct compounds, such as trimethyl-phosphite, orphosphorous acid triamides which contain optionally substitutedaliphatic hydrocarbon radicals as substituents, such as hexa-loweralkylphosphorous acid triamides, for example hexamethyl-phosphorous acidtriamide, the latter preferably in the form of a methanol adduct, ortetracyanoethylene. The splitting of the ozonide, which is usually notisolated, is normally carried out under the conditions which areemployed for its manufacture, that is to say in the presence of asuitable solvent or solvent mixture, and with cooling or slight warming.

Enol compounds of the formula VI can also be present in the tautomericketo form.

An enol compound of the formula VIa can be converted into a compound ofthe formula VIb or VIc by reaction with a heavy metal sulphinate of theformula M^(n+) (⁻ SO₂ -R₅)_(n) or heavy metal thiosulphonate of theformula M^(n+) (⁻ S-SO₂ -R₅)_(n), analogously to the conversion ofcompounds of the formula IVa to compounds of the formula IVb or IVc.

In a resulting compound of the formula VI, a group R₁ ^(a), R₁ ^(b) orR₂ ^(A) can be converted into another group R₁ ^(a), R₁ ^(b) or R₂ ^(A),for which analogous reactions can be used to those appropriate for theconversion of these groups in compounds of the formula IA or IB.

In the 4th stage, a resulting enol compound of the formula VI isconverted into a compound of the formula II by etherification.

To manufacture lower alkyl enol ethers and optionally substitutedα-phenyl-lower alkyl enol ethers of the formula II, the etherifyingreagent used is, for example, a corresponding diazo compound, forexample a diazo-lower alkane, such as diazomethane, diazoethane,diazo-n-butane or an optionally substituted α-phenyl-diazo-lower alkane,for example phenyldiazomethane or diphenyldiazomethane. These reagentsare employed in the presence of a suitable inert solvent, such as analiphatic, cycloaliphatic or aromatic hydrocarbon, such as hexane,cyclohexane, benzene or toluene, a halogenated aliphatic hydrocarbon,for example methylene chloride, a lower alkanol, for example methanol,ethanol or tert.-butanol, or an ether, such as a di-lower alkyl ether,for example diethyl ether, or a cyclic ether, for exampletetrahydrofurane or dioxane, or a solvent mixture, and, depending on thediazo reagent, with cooling, at room temperature or with slight warming,and also, if necessary, in a closed vessel and/or under an inert gasatmosphere, for example a nitrogen atmosphere.

Furthermore it is possible to form lower alkyl enol ethers andoptionally substituted α-phenyl-lower alkyl enol ethers of the formulaII by treating an enol compound of the formula VI with a reactive esterof a corresponding alcohol of the formula R₃ ^(o) -OH. Suitable estersare above all those with strong inorganic or organic acids, such asmineral acids, for example hydrogen halide acids, such as hydrochloricacid, hydrobromic acid or hydriodic acid, and also sulphuric acid orhalogenosulphuric acids, for example fluorosulphuric acid, or strongorganic sulphonic acids, such as lower alkanesulphonic acids which areoptionally substituted, for example by halogen, such as fluorine, oraromatic sulphonic acids, such as, for example, benzenesulphonic acidswhich are optionally substituted, for example by lower alkyl, such asmethyl, halogen, such as bromine, and/or nitro, for examplemethanesulphonic acid, trifluoromethanesulphonic acid orp-toluenesulphonic acid. These reagents, especially di-lower alkylsulphates, such as dimethyl sulphate, as well as lower alkylfluorosulphates, for example methyl fluorosulphate, or optionallyhalogen-substituted methanesulphonic acid lower alkyl esters, forexample trifluoromethanesulphonic acid methyl ester, or correspondingα-phenyl-lower alkyl esters, for example benzyl esters anddiphenylmethyl esters, such as benzyl halides or diphenylmethyl halides,such as chlorides or bromides, are usually employed in the presence of asolvent, such as an optionally halogenated, such as chlorinated,aliphatic, cycloaliphatic or aromatic hydrocarbon for example methylenechloride, an ether, such as dioxane or tetrahydrofurane, or a loweralkanol, such as methanol, or a solvent mixture. At the same timepreferably suitable condensation agents are used, such as alkali metalcarbonates or alkali metal bicarbonates, for example sodium carbonate orbicarbonate or potassium carbonate or bicarbonate (usually together witha sulphate), or organic bases such as, usually sterically hindered,tri-lower alkylamines, for example N,N-diisopropyl-N-ethylamine(preferably together with lower alkyl halogenosulphates, or optionallyhalogen-substituted methanesulphonic acid lower alkyl esters), thereaction being carried out with cooling, at room temperature or withwarming, for example at temperatures of about -20° C. to about 50° C.,and, if necessary, in a closed vessel and/or in an inert gas atmosphere,for example a nitrogen atmosphere.

The etherification reaction can be accelerated substantially by phasetransfer catalysis (see E. V. Dehmlow, Angewandte Chemie 5/1974, page187). Phase transfer catalysts which can be used are quaternaryphosphonium salts and especially quaternary ammonium salts, such asoptionally substituted tetraalkylammonium halides, for exampletetrabutylammonium chloride, bromide or iodide, orbenzyltriethylammonium chloride, in catalytic amounts or in up toequimolar amounts. The organic phase used can be any water-immisciblesolvent, for example one of the optionally halogenated, such aschlorinated, aliphatic, cycloaliphatic or aromatic hydrocarbons, such astrichloroethylene or tetrachloroethylene, dichloroethane,trichloroethane or tetrachloroethane, chlorobenzene and especiallycarbon tetrachloride, or also toluene or xylene. The alkali metalcarbonates or alkali metal bicarbonates suitable for use as condensationagents, for example potassium carbonate or bicarbonate or sodiumcarbonate or bicarbonate, alkali metal phosphates, for example potassiumphosphate, and alkali metal hydroxides, for example sodium hydroxide,can, in the case of compounds sensitive to bases, be added to thereaction mixture by titration so that the pH value remains approximatelybetween 7 and 8.5 during the etherification.

Lower alkyl enol ethers of the formula II can also be prepared bytreating an enol compound of the formula VI with a compound containingtwo or three hydroxyl groups etherified by lower alkyl, of the formulaR₃ ^(o) -O, on the same carbon atom of aliphatic character, that is tosay with a corresponding acetal or ortho-ester, in the presence of anacid agent. Thus, for example, it is possible to use, as etherifyingagents, gem-lower alkoxy-lower alkanes, such as 2,2-dimethoxypropane, inthe presence of a strong organic sulphonic acid, such asp-toluenesulphonic acid, and of a suitable solvent, such as a loweralkanol, for example methanol, or a di-lower alkylsulphoxide or loweralkylenesulphoxide, for example dimethylsulphoxide, or orthoformic acidtri-lower alkyl esters, for example orthoformic acid triethyl ester, inthe presence of a strong mineral acid, for example sulphuric acid, or ofa strong organic sulphonic acid, such as p-toluenesulphonic acid, and ofa suitable solvent, such as a lower alkanol, for example ethanol, or anether, for example dioxane, and compounds of the formula II, wherein R₃^(o) represents lower alkyl, for example methyl or ethyl, can thus beobtained.

The lower alkyl enol ethers of the formula II can also be obtained whenenol compounds of the formula VI are treated with tri-loweralkyl-oxonium salts of the formula (R₃ ^(o))₃ O.sup.⊖ A.sup.⊕ (so-calledMeerwin salts), or di-R₃ -O-carbenium salts of the formula (R₃ ^(o) O)₂CH.sup.⊖ A.sup.⊕, or di-R₃ halonium salts of the formula (R₃ ^(o))₂Hal.sup.⊖ A.sup.⊕, wherein A.sup.⊕ denotes the anion of an acid andHal.sup.⊖ denotes a halonium ion, especially a bromonium ion, and R₃^(o) denotes lower alkyl. Such salts are, above all, tri-loweralkyl-oxonium salts, as well as di-lower alkoxy-carbenium salts ordi-lower alkyl-halonium salts, especially the corresponding salts withcomplex acids containing fluorine, such as the correspondingtetrafluoborates, hexafluophosphates, hexafluoantimonates orhexachloroantimonates. Examples of such reagents are trimethyloxonium ortriethyloxonium hexafluoantimonate, hexachloroantimonate,hexafluophosphate or tetrafluoborate, dimethoxycarbeniumhexafluophosphate or dimethylbromonium hexafluoantimonate. Theseetherifying agents are preferably used in an inert solvent, such as anether or a halogenated hydrocarbon, for example diethyl ether,tetrahydrofurane or methylene chloride, or in a mixture thereof, ifnecessary in the presence of a base, such as an organic base, forexample a preferably sterically hindered tri-lower alkylamine, forexample N,N-diisopropyl-N-ethyl-amine, and with cooling, at roomtemperature or with slight warming, for example at about -20° C. toabout 50° C., if necessary in a closed vessel and/or in an inert gasatmosphere, for example a nitrogen atmosphere.

Compounds of the formula II, wherein the hydroxy protective group R₃^(o) is a 2-oxa-aliphatic or 2-oxa-cycloaliphatic or 2-thia-aliphatic or2-thia-cycloaliphatic hydrocarbon radical are manufactured byacid-catalysed addition reaction, for example addition reactioncatalysed by a strong mineral acid, such as sulphuric acid orhydrochloric acid, of α,β-unsaturated aliphatic or cycloaliphatic ethersor thioethers, such as 1-lower alkoxy-lower alkenes, for example1-methoxyethene or 1-methoxypropene, 1-lower alkylthio-lower alkenes,such as 1-methylthio-ethene or 1-methylthio-propene, oxa- orthia-cyclo-lower alk-2-enes or -2,4-dienes having 5-7 ring atoms, forexample 2,3-dihydrofurane, 2H-pyrane, 3,4-dihydro-2H-pyrane orcorresponding analogous sulphur compounds, with the 3-hydroxyl group ofa compound of the formula VI. The addition reaction can be carried outin an excess of the unsaturated ether or thioether and optionally in aninert organic solvent, for example in an aliphatic, cycloaliphatic oraromatic hydrocarbon, such as pentane, hexane, cyclohexane, benzene,toluene and the like, with exclusion of water.

Silyl ethers or stannyl ethers embraced by the formula II, that is tosay compounds of the formula II, wherein R₃ ^(o) denotes a substitutedsilyl or stannyl group, are obtained in accordance with any processsuitable for the silylation or stannylation of enol groups, for exampleby treatment with a suitable silylating agent, such as adihalogeno-di-lower alkyl-silane, lower alkoxy-loweralkyl-dihalogeno-silane or tri-lower alkyl-silyl halide, for exampledichloro-dimethyl-silane, methoxy-methyl-dichloro-silane, trimethylsilylchloride or dimethyl-tert.-butyl-silyl chloride, such silyl halidecompounds preferably being used in the presence of a base, for examplepyridine, with an optionally N-mono-lower alkylated, N,N-di-loweralkylated, N-tri-lower alkylsilylated or N-lower alkyl-N-tri-loweralkyl-silylated N-(tri-lower alkyl-silyl)-amine (see, for example,British Pat. No. 1,073,530), for example with a hexa-loweralkyl-disilazane, such as hexamethyldisilazane, or with a silylatedcarboxylic acid amide, such as a bis-tri-lower alkyl-silyl-acetamide,for example, bis-trimethylsilyl-acetamide, or trifluorosilyl-acetamide,or with a suitable stannylating agent, such as a bis-(tri-loweralkyl-tin) oxide, for example bis-(tri-n-butyl-tin) oxide, a tri-loweralkyl-tin hydroxide, for example triethyl-tin hydroxide, a tri-loweralkyl-lower alkoxy-tin compound, tetra-lower alkoxy-tin compound ortetra-lower alkyl-tin compound, or a tri-lower alkyl-tin halide, forexample tri-n-butyl-tin chloride (see, for example, NetherlandsPublished Specification 67/11,107).

A compound of the formula IIa, wherein R₃ ^(o) denotes lower alkyl or aprotective radical for a hydroxyl group, can be converted into acompound of the formula IIb or IIc by reaction with a heavy metalsulphinate of the formula M^(n+) (⁻ SO₂ -R₅)_(n) or a heavy metalthiosulphonate of the formula M^(n+) (^(-S-SO) ₂ -R₅)_(n), analogouslyto the conversion of compounds of the formula IVa to IVb or IVc.

In a resulting compound of the formula II, a group R₁ ^(a), R₁ ^(b), R₂^(A) or R₃ can be converted into another group R₁ ^(a), R₁ ^(b), R₂ ^(A)or R₃, for which purpose it is possible to use analogous reactions tothose indicated for the conversion of these groups in the case ofcompounds of the formula IA or IV.

The pharmacologically usable compounds of the present invention can, forexample, be used for the manufacture of pharmaceutical preparationswhich contain an effective amount of the active substance together with,or mixed with, inorganic or organic, solid or liquid, pharmaceuticallyusable excipients which are suitable for enteral administration orpreferably for parenteral administration. Thus, tablets or gelatinecapsules are used which contain the active compound together withdiluents, for example lactose, dextrose, sucrose, mannitol, sorbitol,cellulose and/or glycine, and lubricants, for example silica, talc,stearic acid or salts thereof, such as magnesium stearate or calciumstearate, and/or polyethylene glycol; tablets also contain binders, forexample magnesium aluminium silicate, starches, such as corn starch,wheat starch, rice starch or arrowroot starch, gelatine, tragacanth,methylcellulose, sodium carboxymethylcellulose and/orpolyvinylpyrrolidone and, if desired, disintegrating agents, for examplestarches, agar, alginic acid or a salt thereof, such as sodium alginate,and/or effervescent mixtures, or adsorbents, dyestuffs, flavouringsubstances and sweeteners. Furthermore, the new pharmacologically activecompounds can be used in the form of injectable preparations, forexample preparations which can be administered intravenously, or ofinfusion solutions. Such solutions are, preferably, isotonic aqueoussolutions or suspensions and these can, for example, be manufacturedbefore use from lyophilised preparations which contain the activesubstance by itself or together with an excipient, for example mannitol.The pharmaceutical preparations can be sterilised and/or containauxiliaries, for example preservatives, stabilisers, wetting agentsand/or emulsifiers, solubilising agents, salts for regulating theosmotic pressure and/or buffers. The present pharmaceutical preparationswhich can, if desired, contain further pharmacologically valuablesubstances, are manufactured in a manner which is in itself known, forexample by means of conventional mixing, granulating, dragee-making,dissolving or lyophilising processes, and contain from about 0.1% to100%, especially from about 1% to about 50%, of lyophilised products orup to 100% of the active substance.

In the context of the present description, the organic radicalsdescribed as "lower" contain, unless expressly defined, up to 7,preferably up to 4, carbon atoms; acyl radicals contain up to 20,preferably up to 12, and above all up to 7, carbon atoms.

The examples which follow serve to illustrate the invention. The cephemcompounds mentioned in the examples possess the R-configuration in the6- and 7-position, and the azetidinone compounds mentioned possess theR-configuration in the 3- and 4-position.

EXAMPLE 1

A solution of 60 μl (2 equivalents) of1,5-diazabicyclo[5.4.0]undec-5-ene in 1 ml of tetrahydrofurane is addeddropwise over the course of 5 minutes to a solution of 133 mg (0.2 mM)of an isomer mixture consisting of2-[4-(p-toluenesulphonylthio)-3-phenoxyacetamido-2-oxoazetidin-1-yl]-3-methoxy-crotonicacid p-nitrobenzyl ester and the corresponding isocrotonic acid ester,in the ratio of about 4:1, in 4 ml of dry tetrahydrofurane. Afterstanding at room temperature for 40 minutes, the mixture is diluted with20 ml of benzene, cooled in an icebath and stirred for 10 minutes with10 ml of a 10% strength citric acid solution. The organic layer isseparated off and washed successively with saturated sodium chloridesolution, 10% strength sodium bicarbonate solution and sodium chloridesolution. The solution is dried over magnesium sulphate and concentratedin vacuo, and the resulting yellow oil is purified bychromatography-filtration on 4 g of acid-washed silica gel (2 kg ofsilica gel are stirred three times with 2 l of concentrated hydrochloricacid in each case for 10 minutes, separated from the acid by decanting,washed with distilled water until neutral, rinsed with methanol andactivated for 60 hours at 120° C.), with benzene/ethyl acetate, 5:1, asthe eluting agent. The fractions containing the isomer mixture arecombined and concentrated in vacuo. A semi-solid isomer mixture,consisting of 7β-phenoxyacetamido-3-methoxy-ceph-3-em-4-carboxylic acidp-nitrobenzyl ester and7β-phenoxyacetamido-3-methoxy-ceph-2-em-4-carboxylic acid p-nitrobenzylester in the ratio of about 1:3 is obtained and can be separated intothe two isomers on Woelm silica gel (activity III) with benzene/ethylacetate, 5:1. The faster-running7β-phenoxyacetamido-3-methoxy-ceph-2-em-4-carboxylic acid p-nitrobenzylester is recrystallised from methylene chloride/ether and has a meltingpoint of 129°-131.5° C. The slower-running7β-phenoxyacetamido-3-methoxy-ceph-3-em-4-carboxylic acid p-nitrobenzylester has a melting point of 140.5°-142° C. (from methylenechloride/ether).

The products can be further converted as follows:

A solution, prepared at 0° C., of 555 mg (1.11 mmols) of a crude mixtureconsisting of 7β-phenoxyacetamido-3-methoxy-ceph-2-em-4α-carboxylic acidp-nitrobenzyl ester and7β-phenoxyacetamido-3-methoxy-ceph-3-em-4-carboxylic acid p-nitrobenzylester in the ratio of about 3:1, in 33 ml of tetrahydrofurane, is mixed,whilst stirring, with 16 ml of an 0.1 N potassium hydroxide solutionwhich has been precooled to 0° C. The mixture is stirred for a further 5minutes at 0° C., 100 ml of ice water and 100 ml of precooled methylenechloride are then added and the whole is stirred up briefly. Addition of1 ml of saturated aqueous sodium chloride solution causes the two phasesto separate. The organic phase is separated off, and the aqueous phaseis again washed with 20 ml of methylene chloride, then covered with 50ml of methylene chloride and acidified with 20 ml of 2 N hydrochloricacid. After shaking up, the organic phase is separated off and thehydrochloric acid solution is extracted twice more with 10 ml ofmethylene chloride at a time. The combined methylene chloride extractsare dried over sodium sulphate and evaporated in vacuo. The residue isrecrystallised from methylene chloride/diethyl ether/pentane and gives7β-phenoxyacetamido-3-methoxy-ceph-2-em-4α-carboxylic acid of meltingpoint 142°-145° C.

The starting materials can be obtained as follows:

(a) A solution of 36.6 g (0.1 M) of 6-phenoxyacetamidopenicillanic acid1β-oxide, 11.1 ml (0.11 M) of triethylamine and 23.8 g (0.11 M) ofp-nitrobenzyl bromide in 200 ml of dimethylformamide is stirred for 4hours under nitrogen at room temperature. The reaction solution is thenintroduced into 1.5 l of ice water and the precipitate is filtered off,dried and twice recrystallised from ethyl acetate-methylene chloride.The colourless, crystalline 6-phenoxyacetamidopenicillanic acidp-nitrobenzyl ester 1β-oxide melts at 179°-180° C.

(b) A solution of 5.01 g (10 mM) of 6-phenoxyacetamidopenicillanic acidp-nitrobenzyl ester 1β-oxide and 1.67 g (10 mM) of2-mercaptobenzthiazole in 110 ml of dry toluene is boiled for 4 hoursunder reflux in a nitrogen atmosphere. The solution is concentrated toapprox. 25 ml by distilling off solvent and diluted with approx. 100 mlof ether. The product which has separated out is recrystallised frommethylene chloride/ether and2-[4-(benzthiazol-2-yldithio)-3-phenoxyacetamido-2-oxoazetidin-1-yl]-3-methylene-butyricacid p-nitrobenzyl ester of melting point 138°-141° C. is obtained.

(c) 1.06 g of finely powdered silver nitrate are added to a solution of3.25 g (5.0 mM) of2-[4-(benzthiazol-2-yldithio)-3-phenoxyacetamido-2-oxaazetidin-1-yl]-3-methylenebutyricacid p-nitrobenzyl ester in 200 ml of acetone/water, 9:1 (v/v).Immediately afterwards, a solution of 890 mg (5 mM) of sodiump-toluenesulphinate in 100 ml of the same solvent mixture is introduced(over the course of 10 minutes). A light yellow precipitate formsimmediately. After stirring for one hour at room temperature, themixture is filtered, with addition of Celite. The filtrate is dilutedwith water and twice extracted with ether. The combined ether extractsare dried over sodium sulphate and after concentration give pale yellowsolid2-[4-(p-toluenesulphonylthio)-3-phenoxyacetamido-2-oxoazetidin-1-yl]-3-methylene-butyricacid p-nitrobenzyl ester. Thin layer chromatogram on silica gel(toluene/ethyl acetate, 2:1): Rf value=0.24; IR spectrum (in CH₂ Cl₂):characteristic bands at 3.90, 5.56, 5.70, 5.87, 6.23, 6.53, 6.66, 7.40,7.50, 8.10, 8.72, 9.25 and 10.95μ. The product can be employed withoutfurther purification in the subsequent reaction.

The same compound can also be obtained in accordance with the followingmethods:

(ci) 1.58 g (1.2 equivalents) of silver p-toluenesulphinate are added inportions for 10 minutes to a solution of 3.25 g (5.0 mM) of2-[4-(benzthiazol-2-yldithio)-3-phenoxyacetamido-2-oxoazetidin-1-yl]-3-methylene-butyricacid p-nitrobenzyl ester in 200 ml of acetone/water, 9:1 (v/v). Thesuspension is stirred for one hour at room temperature, filtered andthen further processed as described in Example 1c).2-[4-(p-toluenesulphonylthio)-3-phenoxyacetamido-2-oxoazetidin-1-yl]-3-methylene-butyricacid p-nitrobenzyl ester is obtained in quantitative yield.

Silver p-toluenesulphinate is obtained as a colourless precipitate bycombining aqueous solutions of equimolar amounts of silver nitrate andsodium p-toluenesulphinate. The product is dried in vacuo for 24 hours.

(cii)2-[4-(p-Toluenesulphonylthio)-3-phenoxyacetamido-2-oxoazetidin-1-yl]-3-methylene-butyricacid p-nitrobenzyl ester can also be obtained in quantitative yield,analogously to Example 1ci) from 3.25 g of2-[4-(benzthiazol-2-yldithio)-3-phenoxyacetamido-2-oxoazetidin-1-yl]-3-methylene-butyricacid p-nitrobenzyl ester and 1.87 g (2 equivalents) of copper-IIdi-p-toluenesulphinate.

Copper-II di-p-toluenesulphinate is obtained by reaction of coppersulphate and sodium p-toluenesulphinate (2 equivalents) in water. Afterfiltering off, the salt is dried in vacuo for 12 hours at 60° C.

(ciii)2-[4-(p-Toluenesulphonylthio)-3-phenoxyacetamido-2-oxoazetidin-1-yl]-3-methylene-butyricacid p-nitrobenzyl ester can also be obtained analogously to Example1ci) from 130 mg of2-[4-(benzthiazol-2-yldithio)-3-phenoxyacetamido-2-oxoazetidin-1-yl]-3-methylene-butyricacid p-nitrobenzyl ester and 85 mg (2 equivalents) of tin-IIdi-p-toluenesulphinate.

Tin-II di-p-toluenesulphinate is obtained by reaction of tin-II chloride(2H₂ O) and sodium p-toluenesulphinate in water. After filtering off,and washing with water, the salt is dried in vacuo for about 12 hours at50°-60° C.

(civ)2-[4-(p-Toluenesulphonylthio)-3-phenoxyacetamido-2-oxoazetidin-1-yl]-3-methylene-butyricacid p-nitrobenzyl ester can also be obtained analogously to Example1ci) from 130 mg of2-[4-(benzthiazol-2-yldithio)-3-phenoxyacetamido-2-oxoazetidin-1-yl]-3-methylene-butyricacid p-nitrobenzyl ester and 102 mg (2 equivalents) of mercury-IIdi-p-toluenesulphinate.

Mercury-II di-p-toluenesulphinate is obtained by reaction of mercury-IIdiacetate and sodium p-toluenesulphinate in water. After filtering off,and washing with water, the salt is dried in vacuo for about 12 hours at50°-60° C.

(cv) A solution of 517 mg (1.02 mM) of 6-phenoxyacetamidopenicillanicacid p-nitrobenzyl ester 1β-oxide and 187 mg (1.2 mM) ofp-toluenesulphinic acid in 10 ml of 1,2-dimethoxyethane (or dioxane) isheated under reflux for 4.5 hours in the presence of 3.5 g of amolecular sieve 3A, and in a nitrogen atmosphere, after which a further308 mg (1.98 mM) of p-toluenesulphinic acid, dissolved in 2 ml of1,2-dimethoxyethane, are added in five portions at 45 minute intervals.After 4.5 hours, the reaction mixture is poured into 100 ml of 5%strength aqueous sodium bicarbonate solution and extracted with ethylacetate. The combined organic phases are washed with water and saturatedaqueous sodium chloride solution, dried over magnesium sulphate andconcentrated by evaporation. The residue is chromatographed on silicagel thick layer plates with toluene/ethyl acetate, 2:1, and gives2-[4-(p-toluenesulphonylthio)-3-phenoxyacetamido-2-oxoazetidin-1-yl]-3-methylene-butyricacid p-nitrobenzyl ester.

(cvi) A mixture of 250 mg (0.5 mM) of 6-phenoxyacetamidopenicillanicacid p-nitrobenzyl ester 1β-oxide, 110 mg (0.61 mM) ofp-toluenesulphonyl cyanide and 5 mg (0.022 mM) of benzyltriethylammoniumchloride in 2 ml of dry, peroxide-free dioxane is stirred under argon at110° C. for 4.5 hours. The solvent is evaporated off in vacuo and theyellow oil which remains is chromatographed on acid-washed silica gel.Elution with 30% ethyl acetate in toluene gives2-[4-(p-toluenesulphonylthio)-3-phenoxyacetamido-2-oxoazetidin-1-yl]-3-methylene-butyricacid p-nitrobenzyl ester.

(cvii) A mixture of 110 mg (0.61 mM) of p-toluenesulphonyl cyanide and4.5 mg (0.021 mM) of tetraethylammonium bromide in 1 ml of pure dioxaneis stirred for 30 minutes at 110° C. under argon. A suspension of 250 mg(0.5 mM) of 6-phenoxyacetamidopenicillanic acid p-nitrobenzyl ester1β-oxide in 1 ml of dioxane is then added and the resulting solution isstirred for 4 hours at 110° C. under argon. The solvent is removed invacuo, the crude product is dissolved in ethyl acetate and the solutionis washed with water and with saturated aqueous sodium chloridesolution. The organic phase is dried with magnesium sulphate and freedfrom the solvent in vacuo, giving crude2-[4-(p-toluenesulphonylthio)-3-phenoxyacetamido-2-oxoazetidin-1-yl]-3-methylene-butyricacid p-nitrobenzyl ester.

(d) 1.1 equivalents of ozone are passed into a solution of 1.92 g (3.0mM) of2-[4-(p-toluenesulphonylthio)-3-phenoxyacetamido-2-oxoazetidin-1-yl]-3-methylene-butyricacid p-nitrobenzyl ester in 30 ml of dry methyl acetate, at -78° C.,over the course of 33 minutes. Immediately thereafter, excess ozone isremoved by means of a stream of nitrogen (15 minutes at -78° C.). 2.2 mlof dimethyl sulphide (10 equivalents) are added and the solution iswarmed to room temperature. After standing for 5 hours, the solvent isdistilled off in vacuo and the colourless oil which remains is taken upin 100 ml of benzene. The benzene solution is washed with three 50 mlportions of saturated sodium chloride solution, dried over magnesiumsulphate and concentrated to dryness in vacuo. After recrystallising theresidue from toluene,2-[4-(p-toluenesulphonylthio)-3-phenoxyacetamido-2-oxoazetidin-1-yl]-3-hydroxy-crotonicacid p-nitrobenzyl ester of melting point 159°-160° C. is obtained.

(di) The crude2-[4-(p-toluenesulphonylthio)-3-phenoxyacetamido-2-oxoazetidin-1-yl]-3-methylene-butyricacid p-nitrobenzyl ester obtained according to Example 1.cvii) isdissolved in 20 ml of methyl acetate and ozonised at -70° C. untilstarting material is no longer present, according to a thin layerchromatogram. A stream of nitrogen is then passed through the solutionand the latter is warmed to 0°-5° C. A solution of 300 mg of sodiumbisulphite in 5 ml of water is added and the mixture is stirred for 5minutes until no further ozonide is detectable by means of potassiumiodide/starch paper. The mixture is diluted with ethyl acetate, theaqueous phase is separated off and the organic phase is washed withwater, dried over magnesium sulphate and freed from the solvent invacuo. The crude product is dissolved in 3 ml of methylene chloride and15 ml of toluene are added. The precipitate is filtered off and thefiltrate is concentrated by evaporation in vacuo. The residue isrecrystallised from methanol and gives2-[4-(p-toluenesulphonylthio)-3-phenoxyacetamido-2-oxoazetidin-1-yl]-3-hydroxy-crotonicacid p-nitrobenzyl ester of melting point 159°-160° C.

(e) A solution of 1.93 g of2-[4-(p-toluenesulphonylthio)-3-phenoxyacetamido-2-oxoazetidin-1-yl]-3-oxo-butyricacid p-nitrobenzyl ester (3.0 mM) in 15 ml of dry chloroform is cooledto 0° C. and 6 ml of a solution of diazomethane in ether (0.75 molar,corresponding to 1.5 equivalents) is added over the course of 10minutes. The mixture is stirred for two hours at 0° C., excessdiazomethane is removed by means of a stream of nitrogen and the solventis stripped off in vacuo. The crude product is purified by filtrationthrough Woelm silica gel (activity III, 40-fold amount), usingbenzene/ethyl acetate, 5:1. The colourless oil obtained after distillingoff the solvent crystallises on standing. After recrystallisation frommethylene chloride/ether, an isomer mixture consisting of2-[4-(p-toluenesulphonylthio)-3-phenoxyacetamido-2-oxoazetidin-1-yl]-3-methoxy-crotonicacid p-nitrobenzyl ester and the corresponding isocrotonic acid ester inthe ratio of about 4:1 is obtained. Melting point of the mixture: 155°-156.5° C.

EXAMPLE 2

A solution of 279 mg of2-[4-(p-toluenesulphonylthio)-3-phenoxyacetamido-2-oxoazetidin-1-yl]-3-hydroxy-crotonicacid diphenylmethyl ester (0.428 mmol) in 4 ml of chloroform and 1 ml ofhexamethyldisilazane is heated for one hour under reflux and evaporatedin vacuo, and the oily residue is dried for one hour under a highvacuum. The silylated crude product consists of2-[4-(p-toluenesulphonylthio)-3-phenoxyacetamido-2-oxoazetidin-1-yl]-3-trimethylsilyloxy-crotonicacid diphenylmethyl ester and the corresponding isocrotonic aciddiphenylmethyl ester.

The resulting crude product is taken up in 3 ml of dry chloroform, thesolution is cooled to 0° C. and 0.069 ml (0.47 mmol) of1,5-diazabicyclo[5.4.0]undec-5-ene is added under nitrogen, whilststirring. After a reaction time of 1 hour, the solution is mixed with0.3 ml of acetic acid and diluted with chloroform. The chloroformsolution is washed with dilute sulphuric acid, water and dilute sodiumbicarbonate solution. The aqueous phases are extracted with chloroformand the combined organic phases are dried over sodium sulphate andconcentrated in vacuo. Crude 7β-phenoxyacetamido-3-hydroxy-ceph-3-em-4-carboxylic acid diphenylmethyl ester is obtained. Rf value: 0.13(silicaa gel; toluene/ethyl acetate, 3:1).

The resulting crude product is taken up in methanol and an excess ofdiazomethane solution in ether is added at 0° C. Aftr a reaction time of5 minutes, the solution is concentrated completely and the oily residueis chromatographed on silica gel thick layer plates (toleuene/ethylacetate, 3:1). The silica gel of the zone at Rf=0.19 is extracted withethyl acetate and gives7β-phenoxyacetamido-3-methoxy-ceph-3-em-4-carboxylic acid diphenylmethylester; melting point 120° C. (from ether). IR spectrum (in CHCl₃):3,310, 1,775, 1,700, 1,690 and 1,600 cm⁻¹.

The starting material is prepared as follows:

(a) 100 g (27.3 mM) of 6-phenoxyacetamido-penicillanic acid 1β-oxide,500 ml of dioxane and 58.4 g (30 mM) of diphenylmethyldiazomethane afterabout 2 hours give 6-phenoxyacetamidopenicillanic acid diphenylmethylester 1β-oxide; melting point 144°-146° C. (ethyl acetate/petroleumether).

(b) Analogously to Example 1b), 292 g (55 mM) of6-phenoxyacetamido-penicillanic acid diphenylmethyl ester 1β-oxide and99 g (59.5 mM) of 2-mercaptobenzthiazole give2-[4-(benzthiazol-2-yldithio)-3-phenyoxyacetamido-2-oxoazetidin-1-yl]-3-methylene-butyricacid diphenylmethyl ester; melting point 140°14 141° C. (fromtoluene/ether).

(c) Analogously to Example 1c), 10 g (14.7 mM) of2-[4-(benzthiazol-2-yldithio)-3-phenoxyacetamido-2-oxoazetidin-1-yl]-3-methylene-butyricacid diphenylmethyl ester in 50 ml of ethyl acetate and 4.92 g (24.98mM) of finely powdered silver p-toluenesulphinate on stirring for 7hours at room temperature give 2-[4-(p-toluenesulphonylthio)-3-phenoxyacetamido-2-oxoazetidin-1-yl]-3-methylene-butyricacid diphenylmethyl ester. Rf value=0.28 (silica gel, toluene/ethylacetate, 3:1); IR spectrum (CHCl₃): 1,782, 1,740, 1,695, 1,340 and 1,150cm⁻¹.

2-[4-(p-Toluenesulphonylthio)-3-phenoxyacetamido-2-oxoazetidin-1-yl]-3-methylene-butyricacid diphenylmethyl ester can also be prepared as follows:

(ci) A suspension of 106.5 g of 6-phenoxyacetamido-penicillanic aciddiphenylmethyl ester 1β-oxide and 33.8 g of 2-mercaptobenzthiazole in900 ml of toluene and 9 ml of glacial acetic acid is boiled for 2 hoursunder nitrogen using a water separator, during which time about 4.5 mlof water are separated off. The solution is cooled to room temperature,a total of 85.5 g of silver p-toluenesulphinate is added in portionsover the course of 1 hour and the mixture is then stirred for a further2 hours at 22° C. The mixture is filtered through Hyflo and the filtrateis washed twice with saturated aqueous sodium chloride solution. Theorganic phase is dried over magnesium sulphate, concentrated in vacuo toabout 1 liter, decolorised with 30 g of Norit and concentrated byevaporation. The resulting yellow foam is crystallised from methylenechloride/diethyl ether. Melting point 79°-82° C. Rf value=0.55 (silicagel; toluene/ethyl acetate, 3:1). Further quantities of the substancecan be obtained from the mother liquors by crystallisation frommethylene chloride/diethyl ether.

(d) Analogously to Example 1d), 10.8 g (16.2 mM) of2-[4-(p-toluenesulphonylthio)-3-phenoxyacetamido-2-oxoazetidin-1-yl]-3-methylene-butyricacid diphenylmethyl ester in 1 l of methylene chloride and 1.1equivalents of ozone give2-[4-(p-toluenesulphonylthio)-3-phenoxyacetamido-2-oxoazetidin-1-yl]-3-hydroxy-crotonicacid diphenylmethyl ester; melting point 142°-143° C. (fromether/pentane).

The ozonisation can also be carried out at 0° C:

15.2 mmols of ozone are passed into a solution of 9.23 g (13.8 mmols) of2-[4-p-toluenesulphonylthio)-3-phenoxyacetamido-2-oxoazetidin-1-yl]-3-methylene-butyricacid diphenylmethyl ester in 960 ml of methylene chloride at 0° C. overthe course of 19 minutes. 10 ml of dimethylsulphide are added to theclear solution and the mixture is stirred for 20 minutes at 5° C. Afterconcentrating under a waterpump vacuum, and drying the residue in a highvacuum, a light yellow foam results, which crystallises from methylenechloride/hexane; the melting point of the resulting2-[4-(p-toluenesulphonylthio)-3-phenoxyacetamido-2-oxoazetidin-1-yl]-3-hydroxy-crotonicacid diphenylmethyl ester is about 134°-138° C. The thin layerchromatogram: Rf value ˜0.46 (silica gel; toluene/ethyl acetate, 3:1).

The same compound can also be obtained in accordance with the followingmethods:

(di) A solution of 684 mg (1 mM) of2-[4-(benzthiazol-2-yldithio)-3-phenoxyacetamido-2-oxoazetidin-1-yl]-3-hydroxycrotonicacid diphenylmethyl ester in 20 ml of acetone/water, 9:1 (v/v) isstirred with 341 mg (1.3 mM) of silver p-toluenesulphinate for 60minutes at room temperature. The yellow reaction mixture is mixed with50 ml of acetone and filtered. The filtrate is concentrated byevaporation in vacuo and the residue is chromatographed on 30 g ofacid-washed silica gel using toluene/ethyl acetate, 4:1. The resulting2-[4-(p-toluenesulphonylthio)-3-phenoxyacetamido-2-oxoazetidin-1-yl]-3-hydroxy-crotonic aciddiphenylmethyl ester is recrystallised from ether/pentane and melts at142°-143° C.

(dii) A solution of 72.9 mg (0.1 mM) of the crude ozonide, obtained byozonisation of 68.1 mg (0.1 mM) of2-[4-benzthiazol-2-ylthio)-3-phenoxyacetamido-2-oxoazetidin-1-yl]-3-methylene-butyricacid diphenylmethyl ester in ethyl acetate and evaporation of thesolvent, in 2 ml of acetone/water, 9:1 (v/v) is stirred with 35 mg (1.3equivalents) of silver p-toluenesulphinate for one hour at roomtemperature. The reaction mixture is diluted with 3 of acetone andfiltered. 0.2 ml of dimethylsulphide is added to the filtrate and themixture is stirred for two hours at room temperature (until it gives anegative iodine-starch reaction). After removing the solvent in vacuo,the residue is chromatographed on 3 g of acid-washed silica gel, usingtoluene/ethyl acetate, 4:1. The resulting2-[4-(p-toluenesulphonylthio)-3-phenoxyacetamido-2-oxoazetidin-1-yl]-3-hydroxy-crotonicacid diphenylmethyl ester is recrystallised from ether/pentane and meltsat 142°-143° C. After a further recrystallisation, from methylenechloride/diethyl ether, a melting point of 144°-145° C. (corrected) isobtained; [α]_(D) ²⁰ =-68°±1° (c=1; chloroform); thin layerchromatogram: Rf value=0.81 (silica gel; methylene chloride/ethylacetate, 8:2); UV spectrum (ethyl alcohol): λ_(max) =261 nm (ε=14,400);IR spectrum (Nujol): characteristic bands at 3.00; 5.56; 5.93; 5.98;6.06; 6.19; 6.25; 6.54; 6.70; 6.82; 7.02; 7.47; 8.03; 8.76; 9.53; 10.23;10.60; 12.30; 13.26 and 14.30μ.

EXAMPLE 3

0.12 ml of bis-trimethylsilyl-acetamide (0.508 mmol) is added to asolution of 301 mg (0.462 mmol) of2-[4-(p-toluenesulphonylthio)-3-phenoxyacetamido-2-oxoazetidin-1-yl]-3-hydroxy-crotonicacid diphenylmethyl ester in 3 ml of 1,2-dimethoxyethane under anitrogen atmosphere, and the mixture is stirred for one hour at roomtemperature. The solution is completely concentrated by evaporation andthe oily residue is dried for one hour under a high vacuum. Thesilylated crude product is taken up in 3 ml of dried 1,2-diethoxyethaneand after cooling to 0° C. 0.075 ml (0.508 mmol) of 1,5-diazabicyclo[5.4.0]undec-5-ene is added. After 6 hours' reaction time at 0° C. undera nitrogen atmosphere, 0.3 ml of acetic acid is added and the mixture isdiluted with methylene chloride. The methylene chloride solution iswashed successively with dilute sulphuric acid, water and dilutebicarbonate solution. The aqueous phases are extracted with methylenechloride and the combined organic phases are dried with sodium sulphate,concentrated in vacuo and dried under a high vacuum. Crude7β-phenoxyacetamido-3-hydroxy-ceph-3-em-4-carboxylic acid diphenylmethylester is obtained. An excess of a solution of diazomethane in ether isadded to the solution of the crude product in chloroform at 0° C. andthe mixture is left to stand for 5 minutes at 0° C. It is thenconcentrated completely and the residue is chromatographed on silicagel, as in Example 2.7β-Phenoxyacetamido-3-methoxy-ceph-3-em-4-carboxylic acid diphenylmethylester; Rf value=0.19 (silica gel; toluene/ethyl acetate, 3:1); meltingpoint 120° C. (from ether), IR spectrum (in CHCl₃); 3,310, 1,775, 1,710,1,690 and 1,600 cm⁻¹, is obtained.

EXAMPLE 4

0.045 ml (0.3 mmol) of 1,5-diazabicyclo[5.4.0]undec-5-ene is added to asolution of 100 mg (0.15 mmol) of an isomer mixture consisting of2-[4-(p-toluenesulphonylthio)-3-phenoxyacetamido-2-oxoazetidin-1-yl]-3-methoxy-crotonicacid diphenylmethyl ester and the corresponding isocrotonic acid esterin 4 ml of dry 1,2-dimethoxyethane whilst stirring in a nitrogenatmosphere. The solution is stirred for 40 minutes at room temperatureunder nitrogen and then cooled with ice, and 0.1 ml of acetic acid isadded. The solution, diluted with methylene chloride, is successivelywashed with dilute sulphuric acid, water and dilute bicarbonatesolution. The aqueous phases are extracted with methylene chloride. Thecombined organic phases are dried with sodium sulphate, concentrated andcompletely freed from the solvent under a high vacuum. The oily residueis chromatographed on a silica gel thick layer plate (running agenttoluene/ethyl acetate, 3:1, developed once). The two zones at Rf=0.19and 0.4 respectively are jointly extracted with ethyl acetate and theresulting solution is concentrated completely. An oily product isobtained, which consists of7β-phenoxyacetamido-3-methoxy-ceph-3-em-4-carboxylic acid diphenylmethylester and the isomer7β-phenoxyacetamido-3-methoxy-ceph-2-em-4-carboxylic acid diphenylmethylester in the ratio of 1:4. Rf value=0.14 and 0.32 respectively (silicagel, toluene/ethyl acetate, 3:1); IR spectrum (in CHCl₃): 3,400, 3,310,1,785, 1,770, 1,750, 1,710, 1,690, 1,630 and 1,600 cm⁻¹.

(i) The ratio of resulting ceph-2-em to ceph-3-em derivative depends,inter alia, on the solvent used for the cyclisation, on theconcentration of the starting material and of the1,5-diazabicyclo[5.4.0]undec-5-ene and also on the reaction time. Thetable which follows lists some reactions which were carried outanalogously to the above example, in each case with 100 mg of an isomermixture consisting of about 95% of2-[4-(p-toluenesulphonylthio)-3-phenoxyacetamido-2-oxoazetidin-1-yl]-3-methoxy-isocrotonicacid diphenylmethyl ester and about 5% of the corresponding crotonicacid derivative. The reaction time was 20 minutes in each case and theworking up was carried out analogously to the preceding example.

    ______________________________________                                                                 Equiva-   Ratio of                                                            lents of  resulting                                               Concentration                                                                             1,5-diaza-                                                                              ceph-2-em                                               of starting bicyclo-  to                                                      material    [5.4.0.]  ceph-3-em                                  Solvent      weight/volume                                                                             undec-5-ene                                                                             derivative                                 ______________________________________                                        Acetone      10%         1.5       ˜3:2                                 Toluene      10%         1.5       ˜1:1                                 Ethyl acetate                                                                              10%         1.5       ˜4:3                                 Ethyl acetate                                                                              20%         1.3       ˜4:3                                 Isobutyl methyl                                                                            20%         1.3        ˜9:10                               ketone                                                                        Methylchloroform                                                                           20%         1.3       ˜9:7                                 1,2-Dimethoxyethane                                                                        20%         1.3       ˜6:5                                 ______________________________________                                    

(a) The isomer mixture employed as the starting material can be obtainedanalogously to Example 1e) from 4 g 6.14 mM) of2-[4-(p-toluenesulphonylthio)-3-phenoxyacetamido-2-oxoazetidin-1-yl]-3-hydroxy-crotonicacid diphenylmethyl ester and an excess of diazomethane solution inether. The resulting isomer mixture consisting of2-[4-(p-toluenesulphonylthio)-3-phenoxyacetamido-2-oxoazetidin-1-yl]-3-methyoxy-crotonicacid diphenylmethyl ester and the corresponding isocrotonic aciddiphenylmethyl ester (about 3:1) crystallises from ethyl acetate/pentaneand has a melting point of 150°-152° C.

The isomer mixture employed as the starting material, or the crotonicacid and isocrotonic acid derivative, can also be obtained as follows:

(ai) A solution of 698 mg (1 mM) of an isomer mixture consisting of2-[4-benzthiazol-2-ylthio)-3-phenoxyacetamido-2-oxoazetidin-1-yl]-3-methoxy-crotonicacid diphenylmethyl ester and the corresponding isocrotonic aciddiphenylmethyl ester in 20 ml of acetone/water, 9:1 (v/v) is stirredwith 341 mg (1.3 mM) of silver p-toluenesulphinate for 1 hour at roomtemperature. The yellow reaction mixture is diluted with 50 ml ofacetone and filtered. The filtrate is concentrated by evaporation invacuo and the residue is chromatographed on 30 g of acid-washed silicagel using toluene/ethyl acetate, 2:1. An isomer mixture consisting of2-[4-(p-toluenesulphonylthio)-3-phenoxyacetamido-2-oxoacetidin-1-yl]-3-methoxy-crotonicacid diphenylmethyl ester and2-[4-(p-toluenesulphonylthio)-3-phenoxyacetamido-2-oxoazetidin-1-yl]-3-methoxy-isocrotonicacid diphenylmethyl ester is obtained. (aii)

The reaction described under ai) can also be carried out intetrahydrofurane instead of in acetone/water, in which case the mixturemust be stirred for about 24 hours at room temperature.

(aiii) 0.21 ml (1.2 mM) of ethyl-diisopropylamine and 0.12 ml (1.5 mM)of flurorosulphonic acid methyl ester are added to a solution of 336 mg(0.5 mM) of2[4-(p-toluenesulphonylthio)-3-phenoxyacetamido-2-oxoazetidin-1-yl]-3-hydroxy-crotonicacid diphenylmethyl ester in 4 ml of ethylene chloride at 0° C. and themixture is stirred for 30 minutes at 0° C. and a further 30 minutes atroom temperature. The reaction mixture is diluted with ethyl acetate,washed with saturated aqueous sodium chloride solution and diluteaqueous sodium bicarbonate solution and dried over sodium sulphate. Theresidue which remains after concentrating by evaporation ischromatographed on silica gel. With toluene/ethyl acetate, 4:1, a littlestarting material is first eluted. Thereafter, an isomer mixtureconsisting of2-[4-(p-toluenesulphonylthio)-3-phenoxyacetamido-2-oxoazetidin-1-yl]-3-methoxy-crotonicacid diphenylmethyl ester and the corresponding isocrotonic aciddiphenylmethyl ester is isolated with toluene/ethyl acetate, 1:1.

(aiv) 76 mg (0.55 mM) of potasssium carbonate and 0.088 ml 0.92 mM) ofdimethyl sulphate are added to a solution of 300 mg (0.447 mM) of2-[4-(p-toluenesulphonylthio)-3-phenoxyacetamido-2-oxoazetidin-1-yl]-3-hydroxy-crotonicacid diphenylmethyl ester in 4 ml of acetone and the mixture is stirredfor 5 hours at room temperature. The solution is then diluted with ethylacetate, washed with water and dried over sodium sulphate. Afterremoving the solvent, the residue is recrystallised from ethylacetate/pentane, giving an isomer mixture consisting of2-[4-(p-toluenesulphonylthio)-3-phenoxyacetamido-2-oxoazetidin-1-yl]-3-methoxy-crotonicacid diphenylmethyl ester and the corresponding isocrotonic aciddiphenylmethyl ester.

(av) 1.57 g of N,N'-dinitroso-N,N'-dimethyloxamide are added to asolution of 6.73 g of2-[4-(p-toluenesulphonylthio)-3-phenoxyacetamido-2-oxoazetidin-1-yl]-3-hydroxy-crotonicacid diphenylmethyl ester (crystalline) in 67 ml of absolutetetrahydrofurane at -20° C., and thereafter a solution of 0.57 ml (0.51g) of ethylenediamine in 5 ml of tetrahydofurane is added over thecourse of 15 minutes. After the addition, the mixture is stirred for 1hour at 0° C., 0.53 ml (11 mmole) of glacial acetic acid and 6.7 g ofCelite are added and the whole is filtered. The residue is washed with 5times 20 ml of tetrahydrofurane. The filtrate and the wash liquids arecombined, concentrated to approx. 20 g and mixed with 20 ml of hexane.The crystals are filtered off, washed with tetrahydrofurane/hexane, 1:2,and dried under a high vacuum.

The crystals consist in the main of2-[4-(p-toluenesulphonylthio)-3-phenoxyacetamido-2-oxoazetidin-1-yl]-3-methoxy-isocrotonicacid diphenylmethyl ester. A sample is recrystallised from ethylacetate/diethyl ether and gives the following analytical data: meltingpoint 167°-169° C.; [α]_(D) ²⁰ =-30°±1° (c=1; methylene chloride); thinlayer chromatogram: Rf value=0.57 (silica gel; methylene chloride/ethylacetate/glacial acetic acid, 60:40:1); UV spectrum (ethyl alcohol):λ_(max) =260 mμ (ε=16,600); IR spectrum (Nujol): characteristic bands at2.97; 5.62; 5.90; 6.27; 6.61; 6.66; 7.17; 7.53; 7.70; 7.96; 8.02; 8.20;8.80; 9.20; 10.26; 12.24 and 13.30μ. NMR spectrum (100megacycles/second, in CDCl₃): δ2.32 (s/CH₃); 2.34 (s/CH₃); 3.73(s/OCH₃); 4.30/4.44 (AB; J=5/azetidine-4-CH-); 6.8-7.5 (m/19 aromatic H,NH) ppm.

Apart from a little isocrotonic acid derivative, the mother liquor inthe main contains2-[4-(p-toluenesulphonylthio)-3-phenoxyacetamido-2-oxoazetidin-1-yl]-3-methoxy-crotonicacid diphenylmethyl ester, which after chromatographic purification onsilica gel has a melting point of 146°-148° C. (corrected, from ethylacetate/hexane); NMR spectrum (100 megacycles/second, in CDCl₃): δ2.08(s/vinyl-CH₃); 2.26 (s/aromatic -CH₃); 3.70 (s/-OCH₃); 4.47 (s/OCH₂CO-); 4.94 (dd/J=5 and 8/azetidine-3-CH-); 5.83 (d/J=5/azetidine-4-CH-),6.8-7.5 (m/19 aromatic H, -NH-) ppm; [α]_(D) ²⁰ =+21°±1°; (c=1,methylene chloride).

(avi) 3.78 g (30 mmols) of dimethylsulphate and 30 ml of 20 percentstrength aqueous potassium bicarbonate solution are added to asuspension of 6.72 g (10 mmols) of2-[4-(p-toluenesulphonylthio)-3-phenoxyacetamido-2-oxoazetidin-1-yl]-3-hydroxy-crotonicacid diphenylmethyl ester (crystalline) and 0.36 g (1 mmol) oftetera-n-butylammonium iodide in 100 ml of toluene and the mixture isstirred vigorously for 4 hours at room temperature. During the first 15minutes, the solid dissolves. The mixture is diluted with toluene andwashed with saturated aqueous sodium chloride solution. After drying theorganic phase with sodium sulphate, and concentrating it,crystallisation from ethyl acetate/diethyl ether gives2-[4-(p-toluenesulphonylthio)-3-phenoxyacetamido-2-oxoazetidin-1-yl]-3-methoxy-isocrotonicacid diphenylmethyl ester.

(avii) 1.08 g (3 mmols) of tetrabutylammonium iodide and 1.9 ml (2.52 g,20 mmols) of dimethylsulphate are added to a suspension of 3.36 g (5mmols) of2-[4-(p-toluenesulphonylthio)-3-phenoxyacetamido-2-oxoazetidin-1-yl]-3-hydroxycrotonicacid diphenylmethyl ester (crystalline) in 15 ml of carbon tetrachlorideand 10 ml of water. The mixture is vigorously stirred at roomtemperature and 1 N sodium hydroxide solution is added to it by means ofan automatic titrator in sufficient amount to keep the pH constant at7.0. In the course of 4-5 hours, 1.5-2 equivalents of sodium hydroxidesolution are consumed. The mixture is diluted with ethyl acetate andwater and a little sodium chloride is added. The organic phase is driedover sodium sulphate and concentrated by evaporation. The residue iscrystallised from a little ethyl acetate/hexane, 1:1, and gives2-[4-(p-toluenesulphonylthio)-3-phenoxyacetamido-2-oxoazetidin-1-yl]-3-methoxy-isocrotonicacid diphenylmethyl ester.

The isomer mixture employed as the starting material can also beobtained via the corresponding 2-benzoxazole derivatives as follows:

(aviii) A solution of 10 g of 6-phenoxyacetamido-penicillanic aciddiphenylmethyl ester 1β-oxide and 3 g of 2-mercaptobenzoxazole in 25 mlof dry tetrahydrofurane is completely concentrated by evaporation invacuo. The foam which remains is heated to 120° C. (oil bathtemperature) for 70 minutes, under a waterpump vacuum. The fused residueis cooled and then chromatographed on 500 g of acid-washed silica gel,using toluene/ethyl acetate, 6:1 followed by 3:1.2-[4-(Benzoxazol2-yldithio)-3-phenoxyacetamido-2-oxoazetidin-1-yl]-3-methylenebutyricacid diphenylmethyl ester is obtained in the form of a white foam; IRspectrum (methylene chloride): characteristic bands at 5.6, 5.75, 6.90and 6.7μ.

(aix) Approximately one equivalent of ozone (in the form of an O₂ /O₃mixture) is passed into a solution, cooled to -70° C., of 3.35 g of2-[4-(benzoxazol-2-yldithio)-3-phenoxyacetamido-2-oxazetidin-1-yl]-3-methylene-butyricacid diphenylmethyl ester in 125 ml of ethyl acetate, until startingmaterial is no longer detectable by thin layer chromatography (silicagel; toluene/ethyl acetate, 3:1). The solution is concentrated byevaporation to about 50 ml in vacuo, mixed with 5 ml of dimethylsulphide and stirred until the potassium iodide/starch test no longergives a reaction. The mixture is concentrated by evaporation in vacuo,the residue is dissolved in 150 ml of benzene and the solution is washedwith water. The organic phase is dried over sodium sulphate andconcentrated by evaporation. The residue is chromatographed on 150 g ofacid-washed silica gel, using toluene/ethyl acetate, 4:1.2-[4-(Benzoxazol-2-yldithio)-3-phenoxyacetamido-2-oxoazetidin-1-yl]-3-hydroxy-crotonicacid diphenylmethyl ester is obtained in the form of a white foam; IRspectrum (methylene chloride): characteristic bands at 5.60, 5.90 and6.0μ.

(ax) A solution of diazomethane in ether is added dropwise to a solutionof 1.7 g of2-[4-(benzoxazol-2-yldithio)-3-phenoxyacetamido-2-oxoazetidin-1-yl]-3-hydroxy-crotonicacid diphenylmethyl ester in 12.5 ml of methylene chloride at 0° C.,whilst stirring, until starting material is no longer detectable by thinlayer chromatography (silica gel; toluene/ethyl acetate, 3:1). Themixture is concentrated by evaporation in vacuo and the residue ischromatographed on 80 g of acid-washed silica gel, using toluene/ethylacetate, 2:1. An isomer mixture consisting of2-[4-(benzoxazol-2-yl-dithio)-3-phenoxyacetamido-2-oxoazetidin-1-yl]-3-methoxy-crotonicacid diphenylmethyl ester and the corresponding isocrotonic aciddiphenylmethyl ester in the ratio of about 5:1 is obtained; IR spectrum(methylene chloride): characteristic bands at 5.60, 5.85 sh, 5.90, 6.40and 6.65μ.

(axi) A solution of 682 mg (1 mM) of an isomer mixture consisting of2-[4-(benzoxazol-2-yldithio)-3-phenoxyacetamido-2-oxazetidin-1-yl]-3-methoxy-crotonicacid diphenylmethyl ester and the corresponding isocrotonic aciddiphenylmethyl ester in 20 ml. of acetone/water, 9:1 (v/v) is stirredwith 350 mg (1.3 mM) of silver p-toluenesulphinate for 90 minutes atroom temperature. The mixture is filtered through Celite® and thefiltrate is concentrated to 5 ml in vacuo and extracted with 30 ml ofmethylene chloride. The methylene chloride phase is dried over sodiumsulphate and concentrated by evaporation in vacuo. The residue ischromatographed on 30 g of acid-washed silica gel, using toluene/ethylacetate, 1:1, and gives an isomer mixture consisting of2-[4-(p-toluenesulphonylthio)-3-phenoxyacetamido-2-oxoazetidin-1-yl]-3-methoxy-crotonicacid diphenylmethyl ester and the corresponding isocrotonic aciddiphenylmethyl ester.

EXAMPLE 5

A solution of 300 mg (0.45 mmol) of the crystalline isomer mixture,obtainable according to Example 4a), consisting of2-[4-(p-toluenesulphonylthio)-3-phenoxacetamido-2-oxoazetidin-1-yl]-3-methoxy-crotonicacid diphenylmethyl ester and the corresponding isocrotonic acid ester,in 4 ml of dry 1,2-dimethoxyethane is stirred with 0.134 ml (0.9 mmol)of 1,5-diazabicyclo[5.4.0]undec-5-ene at room temperature undernitrogen. After a reaction time of 40 minutes, the solution is cooled to0° C. and 0.4 ml of acetic acid, followed by 180 mg (1.36 mmols) ofm-chloroperbenzoic acid (85% strength) are added. The solution isstirred for 10 minutes at 0° C. under nitrogen, diluted with chloroformand washed with dilute sulphuric acid/sodium thiosulphate, water anddilute sodium bicarbonate solution. The aqueous phases are extractedwith chloroform and the combined organic phases are dried over sodiumsulphate, concentrated in vacuo and freed from the solvent under a highvacuum. The resulting crude product is separated on silica gel thicklayer plates (running agent ethyl acetate, one development). The silicagel of the zone at Rf=0.51 is extracted with ethyl acetate, theresulting solution is concentrated and the residue is dried under a highvacuum. 7β-Phenoxyacetamido-3-methoxy-ceph-3-em-4-carboxylic aciddiphenylmethyl ester 1β-oxide is obtained as an oily residue whichcrystallises from methylene chloride/pentane, melting point 115°-120° C.

7β-Phenoxyacetamido-3-methoxy-ceph-3-em-4-carboxylic acid diphenylmethylester 1α-oxide can be obtained by extracting the silica gel of the zoneat Rf=0.22 with ethyl acetate, concentrating the solution on a rotaryevaporator and drying the oily residue; melting point 175°-180° C. (fromchloroform).

The same compounds can also be prepared according to Example (i) or(ii):

(i) A solution of 24.7 mg (36 mmols) of the crystalline isomer mixtureobtainable according to Example (4a), consisting of2-[4-(p-toluenesulphonylthio)-3-phenoxyacetamido-2-oxoazetidin-1-yl[-3-methoxy-crotonicacid diphenylmethyl ester and the corresponding isocrotonic acid ester,in 247 ml of dry 1,2-dimethoxyethane is stirred with 8.22 ml (54 mmols)of 1,5-diazabicyclo[5.4.0]undec-5-ene at room temperature undernitrogen. After a reaction time of 40 minutes, the solution is cooled to0° C. and 3.73 ml of formic acid are added, followed by 37.3 ml (108mmols) of performic acid (prepared from 33 ml of hydrogen peroxidesolution (30% strength) and 100 ml of formic acid). The solution isstirred for 10 minutes at 0° C. under nitrogen, diluted with chloroformand washed with dilute sulphuric acid/sodium thiosulphate, water anddilute sodium bicarbonate solution. The aqueous phases are extractedwith chloroform and the combined organic phases are dried over sodiumsulphate, concentrated in vacuo and freed from the solvent under a highvacuum. The resulting crude product is crystallised from ethylenechloride/pentane and gives7β-phenoxyacetamido-3-methoxy-ceph-3-em-4-carboxylic acid diphenylmethylester 1β-oxide of melting point 115°-120° C.

(ii) A solution of 1.5 g (2.19 mmols) of the crystalline isomer mixtureobtainable according to Example 4a), consisting of2-[4-(p-toluenesulphonylthio)-3-phenoxyacetamido-2-oxoazetidin-1-yl]-3-methoxy-crotonicacid diphenylmethyl ester and the corresponding isocrotonic acid ester,in 7.5 ml of dry 1,2-dimethoxyethane, is stirred with 0.43 ml (2.84mmols) of 1,5-diazabicyclo[5.4.0]undec-5-ene at room temperature undernitrogen. After a reaction time of 40 minutes the solution is cooled to0° C. and 0.375 ml (6.55 mmols) of acetic acid are added, followed by0.667 ml (4.8 mmols) of 7.2 N peracetic acid. The solution is stirredfor 20 minutes at 0° C. under nitrogen and 0.24 ml of sodium bisulphitesolution (20% strength) is then added. 22.5 ml of water are added to thereaction mixture whilst stirring vigorously. Hereupon, a mixture of7β-phenoxyacetamido-3-methoxy-ceph-3-em-4-carboxylic acid diphenylmethylester 1β-oxide and 1α-oxide crystallises out. The precipitate isfiltered off, washed with water and dried under a high vacuum.

(iii) 32.9 ml (216 mmols) of 1,5-diazabicyclo[5.4.0]undec-5-ene areadded to a suspension of 98.8 g (144 mmols) of2-[4-(p-toluenesulphonylthio)-3-phenoxyacetamido-2-oxoazetidin-1-yl]-3-methoxy-isocrotonicacid diphenylmethyl ester in 988 ml of 1,2-dimethoxyethane over thecourse of 2 minutes at room temperature, under a nitrogen atmosphere,whilst stirring. The solution, which is now clear, is stirred for afurther 25 minutes at room temperature and then cooled to 0° C. whilstsimultaneously adding 14.9 ml (395 mmols) of formic acid, and aftercooling to -20° C. 149 ml of a mixture of 66 ml of hydrogen peroxide(30% strength) and 134 ml of formic acid (432 mmols of H₂ O₂) are addeddropwise. The reaction mixture is then stirred for 15 minutes at 0° C.and 37 g of sodium thiosulphate dissolved in 500 ml of water are thenadded. About 300 ml of water are added over the course of one hour at 5°C. After stirring for a further 2 to 3 hours at 5° C., the crystallineprecipitate, which consists in the main of7β-phenoxyacetamido-3-methoxy-ceph-3-em-4-carboxylic acid diphenylmethylester 1β-oxide is filtered off, washed with cold water (3° C.) anddiethyl ether and dried over calcium chloride in a high vacuum.

7 liters of water are added to the filtrate at 5° C., whilst stirringvigorously. The initially oily precipitate, which solidifies on standingovernight, and which consists predominantly of7β-phenoxyacetamido-3-methoxy-ceph-3-em-4-carboxylic acid diphenylmethylester 1α-oxide, is filtered off, washed with ice-cold water and driedover calcium chloride in a high vacuum.

(iv) 34.35 g (50 mmols) of2-[4-(p-toluenesulphonylthio)-3-phenoxyacetamido-2-oxoazetidin-1-yl]-3-methoxy-isocrotonicacid diphenylmethyl ester are suspended in 340 ml of tetrahydrofurane at20° C. under a nitrogen atmosphere (the bulk of the material dissolves).After rapid addition of 11.4 ml (75 mmols) of1,5-diazabicyclo[5.4.0]undec-5-ene, the solution is stirred for 15minutes at 20° C., 1.9 ml (30.2 mmols) of glacial acetic acid are thenadded and the mixture is concentrated to dryness in vacuo at 30° C. Thebrown, foamy residue is dissolved in 130 ml of methylene chloride andthe solution is washed successively with 60 ml of water, 30 ml of 0.5 Nhydrochloric acid, 30 ml of water, 30 ml of 1 M NaHCO₃ solution and 30ml of water. The aqueous phases are extracted with twice 10 ml ofmethylene chloride.

The combined methylene chloride phases are cooled to -10° C. withoutfirst drying them, and 7.0 ml of peracetic acid/acetic acid (containing˜50 mmols of peracetic acid) are added slowly (the temperature rising to˜+10° C.). After stirring for 15 minutes at 0° C.-5° C., the excessperacetic acid is destroyed with aqueous sodium thiosulphate. Theaqueous phase is separated off and washed with a little methylenechloride. The solution is dried over magnesium sulphate and concentratedin vacuo. The light yellow residue, consisting of a mixture of7β-phenoxyacetamido-3-methoxy-ceph-3-em-4-carboxylic acid diphenylmethylester 1-oxide and 7β-phenoxyacetamido-3-methoxy-ceph-2-em-4-carboxylicacid diphenylmethyl ester 1-oxide in the ratio of about 2:1, isdissolved in 120 ml of monoglyme at room temperature and 30 ml of waterare added, whereupon 7β-phenylacetamido-3-methoxy-ceph-3-em-4-carboxylicacid diphenylmethyl ester 1μ-oxide first crystallises out. The thickcrystal sludge is first stirred for half an hour and then 150 ml ofwater are added over the course of about 5 hours at room temperature,whilst stirring, whereupon the corresponding 1α-oxide also crystallisesout. After stirring for a total of 17 hours, the mixture is cooled for 1hour in an icebath and then filtered, and the residue is washed with alittle cooled monoglyme/water, 1:1.5. The crystals are dried for 16hours over P₂ O₅ in a high vacuum.7β-Phenoxyacetamido-3-methoxy-ceph-3-em-4-carboxylic acid diphenylmethylester 1β-oxide, to which some of the corresponding 1α-oxide stilladheres, is obtained.

The 1-oxides obtained can be further processed as follows:

(a) A solution of 150 mg (0.275 mmol) of7β-phenoxyacetamido-3-methoxy-ceph-3-em-4-carboxylic acid diphenylmethylester 1β-oxide in 3 ml of methylene chloride and 0.1 ml ofdimethylformamide is cooled to 0° C. and 188 mg (1.37 mmols) ofphosphorus trichloride are then added. The solution is stirred for 30minutes at 0° C., diluted with methylene chloride and washed withaqueous sodium bicarbonate solution. The aqueous phase is extracted withmethylene chloride and the combined organic phases are dried over sodiumsulphate and concentrated in vacuo. The resulting crude7β-phenoxyacetamido-3-methoxy-ceph-3-em-4-carboxylic acid diphenylmethylester is recrystallised from ether; melting point 120° C.

(ai) A suspension of 5.0 g (9.16 mmols) of7β-phenoxyacetamido-3-methoxy-ceph-3-em-4-carboxylic acid diphenylmethylester 1α-oxide in 25 ml of methylene chloride and 1.25 ml ofdimethylacetamide is cooled to 0° C. and 1.69 ml (19.3 mmols) ofphosphorus trichloride are then added. The solution is stirred for 30minutes at 0° C., diluted with ethyl acetate and washed with aqueoussodium bicarbonate solution. The aqueous phase is extracted with ethylacetate and the combined organic phases are dried over sodium sulphateand concenrated in vacuo. The resulting crude7β-phenoxyacetamido-3-methoxy-ceph-3-em-4-carboxylic acid diphenylmethylester is recrystallised from ether; melting point 120° C.

(b) 0.87 ml of anisole is added to a solution of 2.0 g (3.78 mmols) of7β-phenoxyacetamido-3-methoxy-ceph-3-em-4-carboxylic acid diphenylmethylester in 5 ml of methylene chloride and the mixture is cooled to 0° C.and left to stand for 1 hour after adding 1.2 ml of trifluoroaceticacid. The reaction mixture is concentrated in vacuo and the residue iscrystallised from acetone/ether.7β-Phenoxyacetamido-3-methoxy-ceph-3-em-4-carboxylic acid of meltingpoint 170° C. (decomposition) is obtained.

The same compound can also be obtained without isolating the estermentioned under (a):

(bi) A suspension of 3.0 g (5.5 mmols) of a mixture of7βphenoxyacetamido-3-methoxy-ceph-3-em-4-carboxylic acid diphenylmethylester 1β-oxide and 1α-oxide in 15 ml of methylene chloride and 0.75 mlof dimethylacetamide is cooled to 0° C. and 0.966 ml (1.11 mmols) ofphosphorus trichloride is then added. The solution is stirred at 0° C.for 40 minutes 4.65 ml (61 mmols) of trifluoroacetic acid are then addedand stirring is continued for a further 30 minutes at 0° C. The reactionsolution is rendered neutral with saturated sodium bicarbonate solutionand the organic phase is washed with dilute bicarbonate solution. Thecombined aqueous phases are washed twice with ethyl acetate and brightto pH 2.6 with phosphoric acid. The7β-phenoxyacetamido-3-methoxy-ceph-3-em-4-carboxylic acid which hasprecipitated is filtered off, washed with water and dried under a highvacuum; melting point 170° C. (decomposition).

(bii) A suspension of 53.4 g (97.7 mmols) of7β-phenoxyacetamido-3-methoxy-ceph-3-em-4-carboxylic acid diphenylmethylester 1β-oxide [from Example 5iii] in 320 ml of methylene chloride and16 ml of dimethylacetamide is cooled to 0° C. and 17.3 ml (19.8 mmols)of phosphorus trichloride are added slowly. After stirring for 20minutes at 0°-5° C., 80 ml (1.05 mols) of trifluoroacetic acid are addeddropwise. The clear solution is stirred for a further 20 minutes at0°-5° C. and is then diluted with 1,300 ml of ethyl acetate and washedsuccessively with 240 ml of 2 M dipotassium phosphate solution, 100 mlof water and 250 ml of half-saturated aqueous sodium chloride solution.7β-Phenoxyacetamido-3-methoxy-ceph-3-em-4-carboxylic acid is extractedfrom the organic phase with 700 ml of saturated aqueous sodiumbicarbonate solution and the aqueous portion is washed twice with 400 mlof ethyl acetate. The organic phases are extracted twice with a total of250 ml of a solution composed of 50 ml of saturated aqueous sodiumbicarbonate solution, 100 ml of water and 100 ml of saturated aqueoussodium chloride solution. The combined bicarbonate extracts are coveredwith 1,500 ml of ethyl acetate and the pH value of the solution isadjusted to ˜2.5 with 20% strength phosphoric acid, while stirringvigorously. The aqueous phase is re-extracted twice with 500 ml of ethylacetate. The combined organic phases are dried over magnesium sulphate,filtered and concentrated by evaporation in vacuo. The residue, whichcrystallises, is suspended in 130 ml of ethyl acetate and left to standovernight at -10° C. The pale yellow crystals of the resulting7β-phenoxyacetamido-3-methoxy-ceph-3-em-4-carboxylic acid are filteredoff, washed with cooled ethyl acetate and dried to constant weight undera high vacuum.

(biii) A solution of 23.9 g of7β-phenoxyacetamido-3-methoxy-ceph-3-em-4-carboxylic acid diphenylmethylester 1α-oxide [from Example 5iii] in 40 ml of methylene chloride and7.2 ml of dimethylacetamide is cooled to 0° C. and after slowly adding7.8 ml of phosphorus trichloride the mixture is stirred for a further 20minutes at 0°-5° C. 36 ml of trifluoroacetic acid are added dropwise tothe reaction solution, and the mixture is then stirred for a further 20minutes at 0°-5° C. and thereafter worked up as described under Example5 bii). 7β-Phenoxyacetamido-3-methoxy-ceph-3-em-4-carboxylic acid isobtained in the form of a light yellow crystalline material.

(c) 0.7 ml (5.7 mmols) of dimethyl-dichloro-silane is added to asuspension of 2.55 g (7 mmols) of7β-phenoxyacetamido-3-methoxy-ceph-3-em-4-carboxylic acid and 2.9 ml(22.4 mmols) of N,N-dimethylaniline in 11 ml of absolute methylenechloride under nitrogen at 20° C. and the mixture is then stirred for 30minutes at the same temperature. The resulting clear solution is cooledto -20° C., 1.6 g (7.7 mmols) of solid phosphorus pentachloride areadded and the mixture is stirred for 30 minutes. A precooled (-20° C.)mixture of 0.9 ml (7 mmols) of N,N-dimethylaniline and 0.9 ml ofn-butanol is added over the course of 2 to 3 minutes at the sametamperature, 10 ml of precooled (-20° C.) n-butanol are then addedrapidly and the mixture is thereafter stirred for 20 minutes at -20° C.and 10 minutes without cooling. 0.4 ml of water is added at about -10°C., the mixture is stirred for about 10 minutes in an ice-bath (0° C.),11 ml of dioxane are then added and after stirring for a further 10minutes at 0° C. approx. 4.5 ml of tri-n-butylamine are added inportions until samples diluted with water assume a constant pH value of3.5. After stirring for 1 hour at 0° C., the precipitate is filteredoff, washed with dioxane and recrystallised from water/dioxane. Theresulting 7β-amino-3-methoxy-ceph-3-em-4-carboxylic acid hydrochloridedioxanate has a melting point in excess of 300° C. Thin layerchromatogram: Rf value 0.17 (silica gel; system n-butanol/carbontetrachloride/methanol/formic acid/water, 30:40:20:5:5).

(ci) 3.6 ml (3.87 g) of dimethyldichlorosilane are added to a suspensionof 11.75 g of 93 percent strength (corresponding to 10.93 g of 100%strength) 7β-phenoxyacetamido-3-methoxy-ceph-3-em-4-carboxylic acid and13.4 ml (12.73 g) of N,N-dimethylaniline in 47 ml of absolute methylenechloride (distilled over P₂ O₅) at+20° C. under nitrogen, and themixture is then stirred for 30 minutes at the same temperature. Thesolution, which is now clear, is cooled to -18° C./-19° C. and 7.8 g ofsolid phosphorus pentachloride are added, whereupon the internaltemperature rises to -10° C. After stirring for 30 minutes in a bath at-20° C., the clear solution is added dropwise, over the course ofapprox. 7 minutes, to a mixture, cooled to -20° C., of 47 ml ofn-butanol (anhydrous, dried over Sikkan) and 4.4 ml (4.18 g) ofdimethylaniline. Hereupon, the internal temperature rises to -8° C. Themixture is stirred for a further 30 minutes, initially in the bath at-20° C. and subsequently in an icebath (0° C.), so that a final internaltemperature of -10° C. is reached. At this temperature, a mixture of 47ml of dioxane and 1.6 ml of water is added dropwise (duration approx. 5minutes). Hereupon, the product slowly crystallises out. After stirringfor a further 10 minutes, the mixture, in an icebath, is brought to a pHvalue of between 2.2 and 2.4, and kept thereat, by adding approx. 9.5 mlof tri-n-butylamine in portions over the course of approx. 1 hour (thefirst 5 ml being added in the first 5 minutes). Thereafter the productis filtered off and washed in portions with approx. 30 ml. of dioxaneand then with approx. 15 ml of methylene chloride, thus givingcrystalline 7β-amino-3-methoxy-ceph-3-em-4-carboxylic acid hydrochloridedioxanate; melting point above 300° C.; UV spectrum (in 0.1 N sodiumbicarbonate): λ_(max) =270 mμ (ε=7,600); IR spectrum (Nujol);characteristic bands at 5.62; 5.80; 5.88; 6.26; 6.55; 7.03; 7.45; 7.72;7.96; 8.14; 8.26; 8.45; 8.64; 8.97; 9.29; 10.40 and 11.47 mμ; [α]_(D) ²⁰=+134°±10° (c=1; 0.5 N sodium bicarbonate solution).

The zwitter-ion of 7β-amino-3-methoxy-ceph-3-em-4-carboxylic acid can beobtained from the resulting hydrochloride dioxanate by adding 2 N sodiumhydroxide solution to a 20% strength aqueous solution of the dioxanateuntil the pH value is 4.1 (isoelectric point); when filtered off anddried, the product has a melting point in excess of 300° C. UV spectrum(in 0.1 N sodium bicarbonate solution) λ_(max) =270 nm (ε=7,600). Thinlayer chromatogram: Rf value identical with that of the hydrochloride(silica gel, same system); [α]_(D) ²⁰ =+232°±1° (c=1; 0.5 N sodiumbicarbonate solution).

(d) 1.65 ml of bis-(trimethylsilyl)-acetamide are added to a suspensionof 1 g (2.82 mmols) of 7β-amino-3-methoxy-ceph-3-em-4-carboxylic acidhydrochloride dioxanate in 20 ml of dry methylene chloride at roomtemperature under a nitrogen atmosphere. After 40 minutes, the clearsolution is cooled to 0° C. and 900 mg (4.37 mmols) of solidD-α-phenylglycyl chloride hydrochloride are added. Five minutes later,0.7 ml (10 mmols) of propylene oxide is added. The suspension is thenstirred for 1 hour at 0° C. under a nitrogen atmosphere and 0.5 ml ofmethanol is then added, whereupon7β-(D-α-phenylglycylamino)-3-methoxy-ceph-3-em-4-carboxylic acidhydrochloride precipitates in a crystalline form. The hydrochloride isfiltered off and dissolved in 9 ml of water, and the pH of the solutionis adjusted to 4.6 with 1 N sodium hydroxide solution. The dihydrate ofthe inner salt of7β-(D-α-phenylglycylamino)-3-methoxy-ceph-3-em-4-carboxylic acid whichprecipitates, is filtered off, washed with acetone and diethyl ether anddried; melting point 174°-176° C. (decomposition); [α]_(D) ²⁰ =+132°(c=0.714; in 0.1 N hydrochloric acid); thin layer chromatogram (silicagel): Rf value˜0.18 (system: n-butanol/acetic acid/water, 67:10:23). UVspectrum (in 0.1 N aqueous sodium bicarbonate solution) λ_(max) =269μ(ε=7,000); IR spectrum (in mineral oil): characteristic bands at 5.72,5.94, 6.23 and 6.60μ .

(di) 1.37 ml (5.6 mmols) of N,N-bis-(trimethylsilyl)-acetamide are addedto a suspension of 993 mg (4.32 mmols) of7β-amino-3-methoxy-ceph-3-em-4-carboxylic acid (inner salt) in 10 ml ofmethylene chloride and the mixture is stirred for 45 minutes at roomtemperature under a nitrogen atmosphere. The clear solution is cooled to0° C. and 1.11 g (5.4 mmols) of D-α-phenylglycyl chloride hydrochlorideare added. After 5 minutes, 0.4 ml (5.6 mmols) of propylene oxide isadded. The suspension is then stirred for 1 hour at 0° C. under anitrogen atmosphere and thereafter 0.6 ml of methanol is added.7β-(D-α-Phenylglycylamido)-3-methoxy-ceph-3-em-4-carboxylic acidhydrochloride, which crystallises out, is filtered off and dissolved in15 ml of water at 0° C., and the pH of the solution is adjusted to about4 with 5 ml of 1 N sodium hydroxide solution. The solution is warmed toroom temperature and its pH is brought to about 4.8 with triethylamine,whereupon 7β-(D-α-phenylglycylamido)-3-methoxy-ceph-3-em-4-carboxylicacid crystallises out in the form of the dihydrate.

EXAMPLE 6

A solution of 0.228 g (1.5 mM) of 1,5-diazabicyclo[5.4.0]undec-5-ene in10 ml of tetrahydrofurane is added to a solution of 0.697 g (1.0 mM) ofan isomer mixture consisting of2-[4-(benzthiazol-2-yldithio)-3-phenoxyacetamido-2-oxo-azetidin-1-yl]-3-methoxy-crotonicacid diphenylmethyl ester and the corresponding isocrotonic aciddiphenylmethyl ester in 4 ml of dry tetrahydrofurane. The mixture isstirred for 40 minutes at room temperature, diluted with 200 ml ofbenzene and washed successively with dilute hydrochloric acid, sodiumbicarbonate solution and water. The organic phase is dried over sodiumsulphate and the solvent is removed in vacuo. The resulting crudeproduct is chromatographed on 30 g of silica gel which has been washedwith hydrochloric acid. Toluene/ethyl acetate, 7:1, first elutes2-mercaptobenzthiazole and subsequently7β-phenoxyacetamido-3-methoxy-ceph-2-em-4-carboxylic acid diphenylmethylester. IR spectrum (in CH₂ Cl₂): 5.60, 5.74, 5.90 and 8.28μ.

The ester obtained can be converted into the free acid as follows:

(i) A mixture of 53 mg (0.1 mmol) of7β-phenoxyacetamido-3-methoxy-ceph-2-em-4α-carboxylic aciddiphenylmethyl ester, 0.07 ml of trifluoroacetic acid, 0.06 ml ofanisole and 0.5 ml of methylene chloride is stirred for 15 hours at 0°C. The mixture is diluted with 5 ml of pentane/diethyl ether, 3:1, andshaken vigorously. The white, amorphous7β-phenoxyacetamido-3-methoxy-ceph-2-em-4α-carboxylic acid whichprecipitates is filtered off and washed with pentane/diethyl ether, 3:1.IR spectrum (CH₂ Cl₂): 5,60, 5.90 and 8.27μ.

The starting material can be obtained as follows:

(a) 1 equivalent of ozone (diluted with oxygen) is passed into asolution, cooled to -70° C., of 681 mg (1.0 mM) of2-[4-(benzthiazol-2-yldithio)-3-phenoxyacetamido-2-oxoazetidin-1-yl]-3-methylene-butyricacid diphenylmethyl ester in 30 ml of ethyl acetate. The reactionsolution is allowed to warm up, concentrated to 10 ml in vacuo, mixedwith 1.0 ml of dimethyl sulphide and stirred for 15 hours at roomtemperature. Solvent and excess reagent are removed in vacuo and theresidue is chromatographed on 30 g of acid-washed silica gel, usingtoluene/ethyl acetate, 4:1 (15 ml fractions).2-[4-(Benzthiazol-2-yldithio)-3-phenoxyacetamido-2-oxoazetidin-1-yl]-3-hydroxy-crotonicacid diphenylmethyl ester is obtained as a solid amorphous substance.[α]_(D) =130°±1° (CHCl₃ ; c=0.8) IR spectrum (CH₂ Cl₂): 2.95, 5.60,5.92, 6.04 and 8.10μ.

(b) A distilled solution of diazomethane in ether (containing 1.3 mM ofdiazomethane) is added to a solution of crude2-[4-(benzthiazol-2-yldithio)-3-phenoxyacetamido-2-oxoazetidin-1-yl]-3-hydroxy-crotonicacid diphenylmethyl ester, obtained by ozonisation of 681 mg (1.0 mM) of2-[4-(benzthiazol-2-yldithio)-3-phenoxyacetamido-2-oxoazetidin-1-yl]-3-methylene-butyricacid diphenylmethyl ester, in 5 ml of methylene chloride at 0° C. Themixture is stirred for one hour at 0° C. and washed with water, and theorganic layer is dried over sodium sulphate. The solvents are removed invacuo and the residue is chromatographed on 35 g of acid-washed silicagel, using toluene/ethyl acetate, 2:1. An isomer mixture consisting of2-[4-(benzthiazol-2-yldithio)-3-phenoxyacetamido-2-oxoazetidin-1-yl]-3-methoxy-crotonicacid diphenylmethyl ester and the corresponding isocrotonic aciddiphenylmethyl ester is obtained. IR spectrum (in CH₂ Cl₂): 5.60, 5.88,6.67, 9.15 and 9,92μ.

EXAMPLE 7

Analogously to Example 4, 200 mg (0.307 mM) of an isomer mixtureconsisting of2-[4-(p-toluenesulphonylthio)-3-phenoxyacetamido-2-oxoazetidin-1-yl]-3-methoxy-crotonicacid 2,2,2-trichloroethyl ester and the corresponding isocrotonic acid2,2,2-trichloroethyl ester and 0.09 ml (0.6 mM) of1,5-diazabicyclo[5.4.0]undec-5-ene, on stirring for 30 minutes at roomtemperature in 3 ml of 1,2-dimethoxyethane, give an isomer mixtureconsisting of 7β-phenoxyacetamido-3-methoxy-ceph-2-em-4-carboxylic acid2,2,2-trichloroethyl ester and7β-phenoxyacetamido-3-methoxy-ceph-3-em-4-carboxylic acid2,2,2-trichloroethyl ester (in the ratio of about 1:1). Rf values=0.36and 0.18 respectively (silica gel; toluene/ethyl acetate, 3:1).

The starting material can be obtained as follows:

(a) Analogously to Example 1(b), 498 mg (1 mM) of6-phenoxyacetamido-penicillanic acid 2,2,2-trichloroethyl ester and200.7 mg (1.2 mM) of 2-mercaptobenzthiazole give2-[4-(benzthiazol-2-yldithio)-3-phenoxyacetamido-2-oxoazetidin-1-yl]-3-methylene-butyricacid 2,2,2-trichloroethyl ester; melting point 144°-149° C. (frommethylene chloride/pentane), Rf value=0.5 (silica gel; ether).

(b) Analogously to Example 6(a), 647 mg (1 mM) of2-[4-(benzthiazol-2-yldithio)-3-phenoxyacetamido-2-oxoazetidin-1-yl]-3-methylene-butyricacid 2,2,2-trichloroethyl ester and 1.2 equivalents of ozone, withsubsequent splitting of the ozonide with dimethyl sulphide, give2-[4-(benzthiazol-2-yldithio)-3-phenoxyacetamido-2-oxoazetidin-1-yl]-3-hydroxy-crotonicacid 2,2,2-trichloroethyl ester; melting point 129°-130° C.(ether/petroleum ether).

(c) Analogously to Example 6(b), 5 g (7.71 mM) of2-[4-(benzthiazol-2-yldithio)-3-phenoxyacetamido-2-oxoazetidin-1-yl]-3-hydroxy-crotonicacid 2,2,2-trichloroethyl ester and an excess of diazomethane give theisomer mixture consisting of2-[4-(benzthiazol-2-yldithio)-3-phenoxyacetamido-2-oxoazetidin-1-yl]-3-methoxy-crotonicacid 2,2,2-trichloroethyl ester and the corresponding isocrotonic acid2,2,2-trichloroethyl ester; melting point 170°-174° C. (from methylenechloride/ether).

(d) Analogously to Example 1(c), 1.9 g (2.87 mM) of an isomer mixtureconsisting of2-[4-(benzthiazol-2-yldithio)-3-phenoxyacetamido-2-oxoazetidin-1-yl]-3-methoxy-crotonicacid 2,2,2-trichloroethyl ester and the corresponding isocrotonic acid2,2,2-trichloroethyl ester, on stirring for five hours at roomtemperature with 0.8 g (4.05 mM) of silver p-toluenesulphinate in 35 mlof acetonitrile/ethyl acetate, 3:4, give an isomer mixture consisting of2-[4-(p-toluenesulphonylthio)-3-phenoxyacetamido-2-oxoazetidin-1-yl]-3-methoxy-crotonicacid 2,2,2-trichloroethyl ester and the corresponding isocrotonic acid2,2,2-trichloroethyl ester; melting point 155°-158° C. (from ethylacetate/ether).

EXAMPLE 8

0.02 ml (0.16 mmol) of trimethylchlorosilane is added to a solution of100 mg (0.146 mmol) of2-[4-(benzthiazol-2-yldithio)-3-phenoxyacetamido-2-oxoazetidin-1-yl]-3-hydroxy-crotonicacid diphenylmethyl ester in 2 ml of dry methylene chloride at 0° C.0.0477 ml (0.32 mmol) of 1,5-diazabicyclo[5.4.0]undec-5-ene is added tothis solution under nitrogen, whilst stirring, and the mixture isstirred for a further hour at 0° C. After addition of 0.2 ml of aceticacid, the mixture is diluted with methylene chloride. The organic phaseis successively washed with dilute sulphuric acid, water and aqueoussodium bicarbonate solution, dried over sodium sulphate and concentratedto dryness in vacuo.

The resulting crude 7β-phenoxyacetamido-3-hydroxy-ceph-3-em-4-carboxylicacid diphenylmethyl ester is dissolved in methanol and a solution ofdiazomethane in ether is added at 0° C. After 10 minutes, the solutionis carefully concentrated and the residue is dried under a high vacuum.The residue is purified by thick layer chromatography (toluene/ethylacetate, 3:1, silica gel). After eluting the silica gel of the zone atRf=0.17 with ethyl acetate, and concentrating the solution on a rotaryevaporator, 7β-phenoxyacetamido-3-methoxy-ceph-3-em-4-carboxylic aciddiphenylmethyl ester is obtained; melting point 120° C. (from ether).

EXAMPLE 9

A solution of 266 mg (0.5 mM) of a crude mixture consisting of2[4-(benzthiazol-2-yldithio)-3-phenoxyacetamido-2-oxoazetidin-1-yl]-3-methoxy-crotonicacid chloride and2-[4-(benzthiazol-2-yldithio)-3-phenoxyacetamido-2-oxoazetidin-1-yl]-3-methoxy-isocrotonicacid chloride in 5 ml of dry methylene chloride is added dropwise overthe course of 15 minutes at 0° C., whilst stirring, to a solution of0.10 ml of triethylamine in 0.5 ml of dry tert.-butanol and 3 ml ofmethylene chloride. After a further 15 minutes stirring, the reactionmixture is diluted with methylene chloride, washed with water, withdilute hydrochloric acid and again with water, dried over sodiumsulphate and concentrated by evaporation in vacuo. The residue ischromatographed on 10 g of acid-washed silica gel, using toluene/ethylacetate (4:1) as the running agent.7β-Phenoxyacetamido-3-methoxy-ceph-2-em-4-carboxylic acid tert.butylester is obtained. IR spectrum (in CH₂ Cl₂): characteristic bands at5.60, 5.77, 5.90 and 8.29μ.

The starting material can be obtained as follows:

(a) A mixture of 0.7 ml of trifluoroacetic acid, 0.6 ml of anisole and2.5 ml of methylene chloride is added slowly to a solution of 698 mg (1mM) of a mixture consisting of2-[4-(benzthiazol-2-yldithio)-3-phenoxyacetamido-2-oxoazetidin-1-yl]-3-methoxy-crotonicacid diphenylmethyl ester and2-[4-(benzthiazol-2-yldithio)-3-phenoxyacetamido-2-oxoazetidin-1-yl]-3-methoxy-isocrotonicacid diphenylmethyl ester in 1.5 ml of methylene chloride at 0° C.,while stirring. The reaction mixture is stirred for 3 hours at 0° C. andthen shaken with 100 ml of ether/pentane, 1:3, and the precipitate isfiltered off. It consists of a mixture of2-[4-(benzthiazol-2-yldithio)-3-phenoxyacetamido-2-oxoazetidin-1-yl]-3-methoxy-crotonicacid and2-[4-(benzthiazol-2-yldithio)-3-phenoxyacetamido-2-oxoazetidin-1-yl]-3-methoxy-isocrotonicacid, and is washed with 25 ml of ether/pentane, 1:3, and dried invacuo. IR spectrum (in CH₂ Cl₂): characteristic bands at 5.60, 5.80,5.94, 8.55 and 9.95μ.

(b) A solution of 532 mg (1.0 mM) of a mixture consisting of2-[4-(benzthiazol-2-yldithio)-3-phenoxyacetamido-2-oxoazetidin-1-yl]-3-methoxy-crotonicacid and2-[4-(benzthiazol-2-yldithio)-3-phenoxyacetamido-2-oxoazetidin-1-yl]-3-methoxy-isocrotonicacid in 5 ml of dry dioxane, containing 10% of oxalyl chloride, isstirred for 15 hours at room temperature and then concentrated byevaporation in vacuo. The solid, non-crystalline residue, consisting ofa mixture of2-[4-(benzthiazol-2-yldithio)-3-phenoxyacetamido-2-oxoazetidin-1-yl]-3-methoxy-crotonicacid chloride and2-[4-(benzthiazol-2-yldithio)-3-phenoxyacetamido-2-oxoazetidin-1-yl]-3-methoxy-isocrotonicacid chloride can be converted further without additional purification.IR spectrum (in CH₂ Cl₂): characteristic bands at 5.58, 5.90 and 9.95μ.

EXAMPLE 10

A solution of 367 mg (0.5 mM) of a mixture consisting of2-[4-(p-nitrobenzenesulphonylthio)-3-phenoxyacetamido-2-oxoazetidin-1-yl]-3-methoxy-crotonicacid diphenylmethyl ester and the corresponding isocrotonic aciddiphenylmethyl ester, and 152 mg (1.0 mM) of1,5-diazabicyclo[5.4.0]undec-5-ene in 10 ml of dry tetrahydrofurane isstirred for 40 minutes at room temperature. The reaction mixture isdiluted with benzene, washed successively with dilute hydrochloric acid,water and dilute aqueous sodium bicarbonate solution, dried over sodiumsulphate and freed from the solvent in vacuo. The residue ischromatographed on acid-washed silica gel, using toluene/ethyl acetate,7:1, as the running agent, whereby pure7β-phenoxyacetamido-3-methoxy-ceph-2-em-4-carboxylic acid diphenylmethylester is obtained. Subsequent elution with toluene/ethyl acetate, 2:1,results in the isolation of a mixture which in addition to7β-phenoxyacetamido-3-methoxy-ceph-2-em-4-carboxylic acid diphenylmethylester also contains 7β-phenoxyacetamido-3-methoxy-ceph-3-em-4-carboxylicacid diphenylmethyl ester.

The starting materials can be prepared as follows:

(a) Analogously to Example 4(ai), 348.5 mg (0.5 mM) of an isomer mixtureconsisting of2-[4-(benzthiazol-2-ylthio)-3-phenoxyacetamido-2-oxoazetidin-1-yl]-3-methoxy-crotonicacid diphenylmethyl ester and the corresponding isocrotonic aciddiphenylmethyl ester, and 200 mg (0.68 mM) of silverp-nitrobenzenesulphinate, on stirring for one hour at 60° C. in 10 ml ofacetone/water, 9:1, give a mixture consisting of2-[4-(p-nitrobenzenesulphonylthio)-3-phenoxyacetamido-2-oxo-azetidin-1-yl]-3-methoxy-crotonicacid diphenylmethyl ester and the corresponding isocrotonic aciddiphenylmethyl ester.

Silver p-nitrobenzenesulphinate is obtained by combining aqueoussolutions of equimolar amounts of silver nitrate and sodiump-nitrobenzenesulphinate. The precipitate is filtered off and dried invacuo for 24 hours at 50°-60° C.

EXAMPLE 11

Analogously to Example 10, 351.5 mg (0.5 mM) of an isomer mixtureconsisting of2-[4-(p-methoxybenzenesulphonylthio)-3-phenoxyacetamido-2-oxoazetidin-1-yl]-3-methoxy-crotonicacid diphenylmethyl ester and the corresponding isocrotonic aciddiphenylmethyl ester, and 152 mg (1 mM) of1,5-diazabicyclo[5.4.0]undec-5-ene, give a mixture consisting of7β-phenoxyacetamido-3-methoxy-ceph-2-em-4-carboxylic acid diphenylmethylester and 7β-phenoxyacetamido-3-methoxy-ceph-3-em-4-carboxylic aciddiphenylmethyl ester, which can be separated into the two isomers bychromatography.

The starting materials can be obtained as follows:

(a) Analogously to Example 4(ai), 697 mg (1 mM) of an isomer mixtureconsisting of2-[4-(benzthiazol-2-ylthio)-3-phenoxyacetamido-2-oxoazetidin-1-yl]-3-methoxy-crotonicacid diphenylmethyl ester and the corresponding isocrotonic aciddiphenylmethyl ester, and 361 mg (1.3 mM) of silverp-methoxybenzenesulphinate, on stirring for one hour at room temperaturein 20 ml of acetone/water, 9:1, give a mixture consisting of2-[4-(p-methoxybenzenesulphonylthio)-3-phenoxyacetamido-2-oxoazetidin-1-yl]-3-methoxy-crotonicacid diphenylmethyl ester and the corresponding isocrotonic aciddiphenylmethyl ester. IR spectrum (in CH₂ Cl₂): characteristic bands at5.60, 5.88, 6.18 and 8.76μ.

Silver p-methoxybenzenesulphinate is obtained by combining aqueoussolutions of equimolar amounts of silver nitrate and sodiump-methoxybenzenesulphinate. The precipitate is filtered off and dried invacuo for 24 hours at 50°-60° C.

EXAMPLE 12

Analogously to Example 10, 336.3 mg (0.5 mM) of an isomer mixtureconsisting of2-(4-benzenesulphonylthio-3-phenoxyacetamido-2-oxoazetidin-1-yl)-3-methoxy-crotonicacid diphenylmethyl ester and the corresponding isocrotonic aciddiphenylmethyl ester, and 152 mg (1 mM) of1,5-diazabicyclo[5.4.0]undec-5-ene, give a mixture consisting of7β-phenoxyacetamido-3-methoxy-ceph-2-em-4-carboxylic acid diphenylmethylester and 7β-phenoxyacetamido-3-methoxy-ceph-3-em-4-carboxylic aciddiphenylmethyl ester, which can be separated into the two isomers bychromatograhy.

The starting materials can be obtained as follows:

(a) Analogously to Example 4(ai), 697 mg (1 mM) of an isomer mixtureconsisting of2-[4-(benzthiazol-2-ylthio)-3-phenoxyacetamido-2-oxoazetidin-1-yl]-3-methoxy-crotonicacid diphenylmethyl ester and the corresponding isocrotonic aciddiphenylmethyl ester, and 324 mg (1.3 mM) of silver benzenesulphinate,on stirring for 90 minutes at room temperature in 20 ml ofacetone/water, 9:1, give a mixture consisting of2-(4-benzenesulphonylthio-3-phenoxyacetamido-2-oxoazetidin-1-yl)-3-methoxy-crotonicacid diphenylmethyl ester and the corresponding isocrotonic aciddiphenylmethyl ester. IR spectrum (in CH₂ Cl₂): characteristic bands at5.60, 5.88 and 8.74μ.

Silver benzenesulphinate is obtained by combining aqueous solutions ofequimolar amounts of silver nitrate and sodium benzenesulphinate. Theprecipitate is filtered off and dried in vacuo for 24 hours at 50°-60°C.

EXAMPLE 13

Analogously to Example 1, an isomer mixture consisting of7β-phenoxyacetamido-3-methoxy-ceph-3-em-4-carboxylic acid p-nitrobenzylester and 7β-phenoxyacetamido-3-methoxy-ceph-2-em-4-carboxylic acidp-nitrobenzyl ester can be obtained from the isomer mixture consistingof2-[4-(p-toluenesulphonylthio)-3-phenoxyacetamido-2-oxoazetidin-1-yl]-3-methoxy-crotonicacid p-nitrobenzyl ester and the corresponding isocrotonic acid ester,by stirring for 12 to 14 hours at room temperature withtetramethylguanidine in tetrahydrofurane.

EXAMPLE 14

A mixture of 104.5 mg (0.15 mM) of an isomer mixture consisting of2-[4-(benzthiazol-2-ylthio)-3-phenoxyacetamido-2-oxoazetidin-1-yl]-3-methoxy-crotonicacid diphenylmethyl ester and the corresponding isocrotonic aciddiphenylmethyl ester, 35 mg (0.225 mM) of p-toluenesulphinic acid and 80mg (0.525 mM) of 1,5-diazabicyclo[5.4.0]undec-5-ene in 3 ml of drytetrahydrofurane is stirred for 40 minutes at room temperature. Themixture is diluted with benzene and washed successively with dilutehydrochloric acid, with dilute aqueous sodium chloride solution, with0.5 N sodium hydroxide solution and again with dilute aqueous sodiumchloride solution. The organic phase is dried over sodium sulphate andfreed from the solvent in vacuo. Chromatography of the residue on 3.5 gof acid-washed silica gel, using toluene/ethyl acetate, 7:1, first givespure 7β-phenoxyacetamido-3-methoxy-ceph-2-em-4α-carboxylic aciddiphenylmethyl ester. Toluene/ethyl acetate, 2:1, subsequently elutes7β-phenoxyacetamido-3-methoxy-ceph-3-em-4-carboxylic acid diphenylmethylester.

EXAMPLE 15

A mixture of 141 mg (0.2 mM) of2-[4-(o-methoxybenzenesulphonylthio)-3-phenoxacetamido-2-oxoazetidin-1-yl]-3-methoxy-crotonicacid diphenylmethyl ester and 61 mg (0.4 mM) of1,4-diazabicyclo[5.4.0]undec-5-ene in 4 ml of dry tetrahydrofurane isstirred for 70 minutes at room temperature. Working up analogously toExample 10 gives a crude mixture consisting of7β-phenoxyacetamido-3-methoxy-ceph-2-em-4α-carboxylic aciddiphenylmethyl ester and7β-phenoxyacetamido-3-methoxy-ceph-3-em-4-carboxylic acid diphenylmethylester in the ratio of about 4.4:1, which can be separated into the twoisomers by chromatography on silica gel, analogously to Example 10.

The two compounds are produced in approximately the same ratio if 141 g(0.2 mM) of2-[4-(o-methoxybenzenesulphonylthio)-3-phenoxyacetamido-2-oxoazetidin-1-yl]-3-methoxyisocrotonicacid diphenylmethyl ester are treated analogously.

The two isomeric starting materials can be obtained as follows:

(a) 3.49 g (5 mM) of an isomer mixture consisting of2-[4-(benzthiazol-2-ylthio)-3-phenoxyacetamido-2-oxoazetidin-1-yl]-3-methoxy-crotonicacid diphenylmethyl ester and the corresponding isocrotonic aciddiphenylmethyl ester in the ratio of about 4:1 are stirred with 1.82 g(6.5 mM) of silver o-methoxybenzenesulphinate in 100 ml ofacetone/water, 9:1, for 130 minutes at room temperature. The mixture isfiltered and the filtrate is concentrated by evaporation in vacuo. Theresidue is chromatographed on 140 g of acid-washed silica gel, usingtoluene/ethyl acetate, 1:1. 50 ml fractions are collected; of these,fractions 7 to 13 contain pure2-[4-(o-methoxybenzenesulphonylthio)-3-phenoxyacetamido-2-oxoazetidin-1-yl]-3-methoxy-isocrotonicacid diphenylmethyl ester, IR spectrum (CH₂ Cl₂): 5.60, 5.90, 8.72 and9.15μ, and fraction 25 and the subsequent fractions give pure2-[4-(o-methoxybenzenesulphonylthio)-3-phenoxyacetamido-2-oxoazetidin-1-yl]-3-methoxy-crotonicacid diphenylmethyl ester, IR spectrum (CH₂ Cl₂): 5.60, 5.90, 8.20,8.30, 8.72, and 9.80μ. Fractions 14 to 24 contain mixtures of the twoisomers.

EXAMPLE 16

A mixture of 57 mg (0.1 mM) of crude2-[4-(o-methoxybenzenesulphonylthio)-3-phenoxyacetamido-2-oxoazetidin-1-yl]-3-methoxy-isocrotonicacid chloride and 43 mg (0.3 mM) of 1,5-diazabicyclo[5.4.0]undec-5-enein 2 ml of dry methylene chloride is stirred for 80 minutes at roomtemperature. The mixture is diluted with methylene chloride, washed withdilute hydrochloric acid and water, dried over sodium sulphate and freedfrom the solvent in vacuo. The residue is dissolved in 0.5 ml ofmethylene chloride, 5 ml of pentane/diethyl ether, 3:1, are added, andthe mixture is shaken. The precipitate is filtered off and washed withpentane/diethyl ether, 3:1. It consists of fairly pure7β-phenoxyacetamido-3-methoxy-ceph-2-em-4-carboxylic acid.

The starting material can be obtained as follows:

(a) A mixture of 703 mg (1 mM) of pure2-[4-(o-methoxybenzenesulphonylthio)-3-phenoxyacetamido-2-oxoazetidin-1-yl]-3-methoxy-isocrotonicacid diphenylmethyl ester, 0.7 ml of trifluoroacetic acid and 0.66 ml ofanisole in 4 ml of methylene chloride is stirred for 3 hours at 0° C. 50ml of pentane/diethyl ether, 3:1, are then added to the mixture and thewhole is shaken vigorously. The white precipitate of pure2-[4-(o-methoxybenzenesulphonylthio)-3-phenoxyacetamido-2-oxoazetidin-1-yl]-3-methoxy-isocrotonicacid is filtered off and washed with pentane/diethyl ether, 3:1. IRspectrum (CH₂ Cl₂): 5.60, 5.93, 6.25 and 8.72μ.

(b) One drop of dimethylformamide in dioxane is added to a solution of54 mg (0.1 mM) of2-[4-(o-methoxybenzenesulphonylthio)-3-phenoxyacetamido-2-oxoazetidin-1-yl]-3-methoxyisocrotonicacid in 0.5 ml of a 10% strength solution of oxalyl chloride in dioxane,whereupon an evolution of gas occurs immediately. The mixture is stirredfor 2 hours at room temperature and the solvent and the excess oxalylchloride are evaporated off in vacuo. The residue is dried in a highvacuum and gives2-[4-(o-methoxybenzenesulphonylthio)-3-phenoxyacetamido-2-oxoazetidin-1-yl]-3-methoxy-isocrotonicacid chloride in the form of a slightly orange-coloured foam, IRspectrum (CH₂ Cl₂): 5.60, 5.90 and 8.70μ.

EXAMPLE 17

A solution of 200 mg (0.254 mM) of2-[4-(p-toluenesulphonylthio)-3-(D-α-tert.-butoxycarbonylamino-.alpha.-phenylacetylamino)-2-oxoazetidin-1-yl]-3-methoxy-crotonicacid diphenylmethyl ester in 2 ml of dimethylformamide is stirred with57 μl (0.38 mM) of 1,5-diazabicyclo[5.4.0]undec-5-ene for 30 minutes atroom temperature, ethyl acetate is then added and the mixture is washedwith water and 2 N hydrochloric acid until it gives an acid reaction,and with saturated aqueous sodium chloride solution until it gives aneutral reaction. The organic phase is dried over sodium sulphate andconcentrated by evaporation in vacuo. The residue is chromatographed onsilica gel thick layer plates, using toluene/ethyl acetate, 1:1, as therunning agent.7β-(D-α-tert.butylcarbonylamino-α-phenylacetylamino)-3-methoxy-ceph-2-em-4α-carboxylicacid diphenylmethyl ester of melting point 166°-168° C. (methylenechloride/pentane); thin layer chromatogram (silica gel; diethyl ether):Rf value˜0.51; UV spectrum (in ethanol): λ_(max) =257 mμ (ε=3,500); IRspectrum (in methylene chloride): characteristic bands at 2.96, 5.63,5.74, 5.85 (shoulder), 5.92, 6.16, 6.64 and 6.72μ; and7β-(D-α-tert.butylcarbonylamino-α-phenyl-acetylamino)-3-methoxy-ceph-3-em-4-carboxylicacid diphenylmethyl ester of melting point 162°-163° C. (diethyl ether);thin layer chromatogram: Rf value: ˜0.33 (silica gel: diethyl ether); UVspectrum (in ethanol) λ_(max) =265 mμ (ε=6,600); 280 mμ (shoulder)(ε=6,200); IR spectrum (in methylene chloride): 2.92, 5.58, 5.64(shoulder), 5.82, 6.22 and 6.67μ are obtained.

The compounds obtained can be converted further as follows:

(a) A mixture of 8.8 g of7β-(D-α-tert.butoxycarbonylamino-α-phenyl-acetylamino)-3-methoxy-3-cephem-4-carboxylicacid diphenylmethyl ester. 8.6 ml of anisole and 145 ml oftrifluoroacetic acid is stirred for 15 minutes at 0° C., 400 ml ofpre-cooled toluene are then added and the mixture is concentrated byevaporation under reduced pressure. The residue is dried under a highvacuum, digested with diethyl ether and filtered off. This gives thetrifluoroacetate of7β-(D-α-phenyl-glycylamino)-3-methoxy-3-cephem-4-carboxylic acid in theform of a powder. The material is dissolved in 20 ml of water, thesolution is washed with twice 25 ml of ethyl acetate and the pH isadjusted to a value of about 5 with a 20% strength solution oftriethylamine in methanol, whereupon a colourless precipitate forms.This mixture is stirred for one hour in an icebath, 20 ml of acetone arethen added and the whole is left to stand for 16 hours at about 4° C.The colourless precipitate is filtered off, washed with acetone anddiethyl ether and dried under reduced pressure. This gives, in the formof a micro-crystalline powder,7β-(D-α-phenyl-glycylamino)-3-methoxy-3-cephem-4-carboxylic acid as theinner salt, which furthermore is present in the form of a hydrate,melting point 174°-176° C. (with decomposition); [α]_(D) ²⁰ =+149°(c=1.03 in 0.1 N hydrochloric acid); thin layer chromatogram (silicagel; development with iodine): Rf˜0.36 (system:n-butanol/pyridine/acetic acid/water, 40:24:6:30); ultravioletabsorption spectrum (in 0.1 N aqueous sodium bicarbonate solution):λ_(max) =267μ (ε=6,200); infra-red absorption spectrum (in mineral oil):characteristic bands, inter alia, at 5.72μ, 5.94μ, 6.23μ and 6.60μ.

(b) A mixture of 0.063 g of7β-(D-α-tert.butoxycarbonylamino-α-phenylacetylamino)-3-methoxy-2-cephem-4α-carboxylicacid diphenylmethyl ester, 0.1 ml of anisole and 1.5 ml oftrifluoroacetic acid is left to stand for 15 minutes at 0° C. and isthen concentrated by evaporation under reduced pressure. The residue isdigested with diethyl ether, filtered off and dried. The colourless andpulverulent trifluoroacetate of7β-(D-α-phenylglycylamino)-3-methoxy-2-cephem-4α-carboxylic acid, thusobtainable, is dissolved in 0.5 ml of water and the pH of the solutionis adjusted to a value of about 5 by dropwise addition of a 10% strengthsolution of triethylamine in methanol. The mixture is stirred for onehour in an icebath and the colourless precipitate is filtered off anddried in a high vacuum. This gives7β-(D-α-phenylglycylamino)-3-methoxy-2-cephem-4α-carboxylic acid as theinner salt, thin layer chromatogram (silica gel; development withiodine): Rf˜0.44 (system: n-butanol/pyridine/acetic acid/water,40:24:6:30); ultraviolet absorption spectrum (in 0.1 N aqueous sodiumbicarbonate solution): λ_(shoulder) =260μ.

(c) A solution of 0.20 g of 3-chloro-perbenzoic acid in 5 ml ofmethylene chloride is added to a solution, cooled to 0° C., of 0.63 g of7β-(D-α-tert.-butoxycarbonylamino-α-phenylacetylamino)-3-methoxy-2-cephem-4α-carboxylicacid diphenylmethyl ester in 25 ml of methylene chloride. The mixture isstirred for 30 minutes at 0° C., 50 ml of methylene chloride are addedand the whole is washed successively with 25 ml of a saturated aqueoussodium bicarbonate solution and 25 ml of a saturated aqueous sodiumchloride solution. The organic phase is dried over sodium sulphate andconcentrated by evaporation under reduced pressure. The residue iscrystallised from a mixture of methylene chloride and diethyl ether;this gives7β-(D-α-tert.-butoxycarbonylamino-α-phenylacetylamino)-3-methoxy-3-cephem-4-carboxylicacid diphenylmethyl ester 1-oxide in the form of colourless needles,melting point 172°-175° C.; thin layer chromatogram (silica gel):RF˜0.44 (system: ethyl acetate; development with iodine vapour);ultraviolet absorption spectrum (in ethanol): λ_(max) =277 mμ (ε=7,200);infra-red absorption spectrum (in methylene chloride): characteristicbands at 2.96μ, 5.56μ, 5.71μ, 5.83μ, 5.90μ, 6.27μ and 6.67μ.

(d) 2.80 g of phosphorus trichloride are added to a solution, cooled to-10° C., of 1.30 g of7β-(D-α-tert.-butoxycarbonylamino-α-phenylacetylamino)-3-methoxy-3-cephem-4-carboxylicacid diphenylmethyl ester 1-oxide in 30 ml of dimethylformamide, whilstexcluding air. After standing for 15 minutes, the reaction mixture ispoured out onto a mixture of ice and an aqueous dipotassium hydrogenphosphate solution; the aqueous mixture is extracted with twice 100 mlof ethyl acetate. The organic extract is washed with a saturated aqueoussodium chloride solution, dried over sodium sulphate and evaporated. Theresidue is chromatographed on silica gel; amorphous7β-(D-α-tert.-butoxycarbonylamino-α-phenylacetylamino)-3-methoxy-3-cephem-4-carboxylicacid diphenylmethyl ester is eluted with diethyl ether as a substancewhich is pure according to thin layer chromatography, Rf˜0.39 (system:diethyl ether; development with iodine vapour); [α]_(D) =1°±1° (c=0.981in chloroform); ultraviolet absorption spectrum (in ethanol): λ_(max)=264μ (ε=6,300); infra-red absorption spectrum (in methylene chloride):characteristic bands at 2.94μ, 5.62μ, 5.84μ, 5.88μ, 6.25μ and 6.70μ.

The starting material can be obtained as follows:

(e) 16.5 ml (0.12 mmol) of chloroformic acid isobutyl ester are added toa solution, cooled to -15° C., of 31.2 g (0.12 mmol) ofD-N-tert.butoxycarbonyl-phenylglycine and 16.7 ml (0.12 mmol) oftriethylamine in 300 ml of tetrahydrofurane and the mixture is stirredfor 30 minutes at -10° C. A solution of 21.6 g (0.10 mmol) of6-amino-penicillanic acid and 15.4 ml (0.11 mmol) of triethylamine in300 ml of tetrahydrofurane/water, 2:1, is then added. The reactionmixture is stirred for 1 hour at 0° C. and 2 hours at room temperaturewhilst keeping the pH value constant at approx. 6.9 by addingtriethylamine. The reaction mixture is adjusted to pH 2.0 at 5° C. bymeans of phosphoric acid and is saturated with sodium chloride andextracted with three times 500 ml of ethyl acetate; the organic phase iswashed with saturated aqueous sodium chloride solution, dried oversodium sulphate and concentrated by evaporation. The crudeN-tert.butoxycarbonyl-ampicillin obtained in the form of a light yellowfoam has an Rf value of ˜0.65 in a thin layer chromatogram (silica gel;ethyl acetate/n-butanol/pyridine/acetic acid/water, 42:21:21:6:10).

(f) 21.6 ml of 30% strength hydrogen peroxide (0.25 M) are added to asolution of 57.22 g of crude N-tert.butoxycarbonyl-ampicillin in 100 mlof glacial acetic acid over the course of 10 minutes and the mixture isstirred for 2.5 hours at room temperature. The reaction mixture is thenpoured onto 2 l of ice water and the N-tert.butoxycarbonyl-ampicillin1-oxide obtained in the form of a voluminous precipitate is filteredoff, well washed with water and dried in vacuo. A further quantity ofcrude N-tert.butylcarbonyl-ampicillin 1-oxide can be obtained byextracting the filtrate with ethyl acetate. Thin layer chromatogram(silica gel; ethyl acetate/n-butanol/pyridine/acetic acid/water,42:21:21:6:10): Rf value˜0.30.

(g) A solution of 42 g (0.23 M) of diphenyldiazomethane in 130 ml ofdioxane is added to a mixture of 67.7 g of crudeN-tert.butoxycarbonyl-ampicillin 1-oxide in 380 ml of dioxane and thewhole is stirred for 2.5 hours at room temperature. After adding 5 ml ofglacial acetic acid, the mixture is concentrated by evaporation invacuo. The residue is digested with petroleum ether, the petroleum etherextract is discarded and the residue is crystallised from methylenechloride/ether/hexane. N-tert.Butoxycarbonyl-ampicillin 1-oxidediphenylmethyl ester of melting point 164°-166° C. is obtained; [α]_(D)²⁰ =+117°±1° (c=1, CHCl₃); IR spectrum (methylene chloride):characteristic bands at 2.91, 2.94, 5.54, 5.69, 5.82 (shoulder), 5.88,6.60 and 6.68μ; thin layer chromatogram: Rf value˜0.23 (silica gel;toluene/ethyl acetate, 3:1).

(h) A mixture of 11.2 g (17.7 mmols) ofN-tert.-butoxycarbonyl-ampicillin 1-oxide diphenylmethyl ester and 3.26g (19.5 mmols) of mercaptobenzthiazole in 170 ml of toluene is boiledfor 3 hours in a reflux apparatus equipped with a water separator, andis then concentrated by evaporation. The residue is chromatographed onsilica gel, using toluene/ethyl acetate, 3:1, as the eluting agent andgives amorphous2-[4-(benzthiazol-2-yldithio)-3-(α-tert.butoxycarbonylamino-α-phenylacetylamino)-2-oxoazetidin-1-yl]-3-methylene-butyricacid diphenylmethyl ester, thin layer chromatogram; Rf value˜0.37(silica gel; toluene/ethyl acetate, 3:1); IR spectrum (methylenechloride): characteristic bands at 2.94, 5.64, 5.76, 5.86 (shoulder),5.91 and 6.71μ.

(i) 0.868 g (3.46 mmols) of silver toluenesulphinate is added to asolution of 2.34 g (3.0 mmols) of2-[4-(benzthiazol-2-yldithio)-3-(α-tert.butoxycarbonylamino-α-phenylacetylamino)-2-oxoazetidin-1-yl]-3-methylene-butyricacid diphenylmethyl ester in 30 ml of acetone/water, 9:1, at 0° C., andthe mixture is stirred for 1 hour in an icebath. The precipitate whichhas separated out is filtered off. The filtrate is taken up in tolueneand extracted by shaking with saturated aqueous sodium chloridesolution. The organic phase is dried over sodium sulphate and, afterevaporation, gives amorphous2-[4-(p-toluenesulphonylthio)-3-(α-tert.butoxycarbonylamino-α-phenylacetylamino)-2-oxoazetidin-1-yl]-3-methylene-butyricacid diphenylmethyl ester; thin layer chromatogram: Rf value˜0.33(silica gel; toluene/ethyl acetate, 3:1); IR spectrum (methylenechloride): characteristic bands at 2.93, 5.57, 5.70, 5.82, 6.21 and6.65μ.

(j) An ozone/oxygen stream (0.5 mmol per minute) is passed for 7 minutesinto a solution, cooled to -70° C., of 2.30 g (3.0 mmols) of2-[4-(p-toluenesulphonylthio)-3-(α-tert.butoxycarbonylamino-α-phenylacetylamino)-2-oxoazetidin-1-yl]-3-methylene-butyricacid diphenylmethyl ester in 230 ml of methylene chloride. After adding1 ml of dimethyl sulphide, the solution is stirred for a further hourwithout cooling and is then concentrated by evaporation in vacuo. Theresidue is recrystallised from methylene chloride/ether/hexane and gives2-[4-(p-toluenesulphonylthio)-3-(α-tert.butoxycarbonylamino-α-phenylacetylamino)-2-oxoazetidin-1-yl]-3-hydroxy-crotonicacid diphenylmethyl ester of melting point 182°-184° C; UV spectrum(ethanol): λ_(max) =259 mμ (ε=13,400); IR spectrum (methylene chloride):characteristic bands at 2.92, 5.59, 5.83, 5.92, 6.03 (shoulder), 6.18and 6.68μ; thin layer chromatogram: Rf value˜0.55 (silica gel;toluene/ethyl acetate, 1:1).

(k) A solution of 0.54 g (0.7 mmol) of2-[4-(p-toluenesulphonylthio)-3-(α-tert.butoxycarbonylamino-α-phenylacetylamino)-2-oxoazetidin-1-yl]-3-hydroxy-crotonicacid diphenylmethyl ester in 20 ml of methylene chloride/methanol, 1:1,is stirred for 15 minutes with an excess of a solution of diazomethanein ether at 0° C. and is then concentrated by evaporation in vacuo.Preparative layer chromatography of the residue on silica gel, usingtoluene/ethyl acetate, 1:1, as the running agent, and elution of thezone which is visible in UV light gives2-[4-(p-toluenesulphonylthio)-3-(α-tert.butoxycarbonylamino-α-phenylacetylamino)-2-oxoazetidin-1-yl]-3-methoxy-crotonicacid diphenylmethyl ester, which is recrystallised from methylenechloride/diethyl ether/hexane. Melting point 204°-206° C.; UV spectrum(ethanol): λ_(max) =259 mμ (ε=16,000); IR spectrum (Nujol):characteristic bands at 2.93, 5.58, 5.80, 5.84, 5.93, 6.24 and 6.57μ;thin layer chromatogram: Rf value˜0.33 (silica gel; toluene/ethylacetate, 1:1).

EXAMPLE 18

A mixture of 670 mg (1 mmol) of2-[4-(p-toluenesulphonylthio)-3-phenylacetamido-2-oxoazetidin-1-yl]-3-methoxycrotonicacid diphenylmethyl ester, 6.7 ml of 1,2-dimethoxyethane and 0.22 ml of1,5-diazabicyclo[5.4.0]undec-5-ene is stirred for 25 minutes at roomtemperature under a nitrogen atmosphere. The reaction mixture is dilutedwith toluene, washed successively with 2 N hydrochloric acid, saturatedaqueous sodium bicarbonate solution and saturated aqueous sodiumchloride solution, dried over sodium sulphate and concentrated byevaporation in vacuo. The residue, after preparative thick layerchromatography on silica gel using toluene/ethyl acetate, 1:1, gives7β-phenylacetamido-3-methoxy-ceph-2-em-4α-carboxylic acid diphenylmethylester of melting point 166°-169° C. (from methylene chloride/hexane), UVspectrum (ethanol): λ_(max) =258 mμ (ε=4,500), IR spectrum (methylenechloride) characteristic bands at 2.93, 5.62, 5.73, 5.93 and 6.66μ, Rfvalue˜0.54 (silica gel; system toluene/ethyl acetate, 1:1), andamorphous 7β-phenylacetamido-3-methoxy-ceph-3-em-4-carboxylic aciddiphenylmethyl ester, UV spectrum (ethanol): λ_(max) =258 mμ (ε=6,350),264 mμ (β=6,350), 282 mμ (ε=5,600) (shoulder), IR spectrum (methylenechloride): characteristic bands at 2.94, 5.63, 5.83, 5.94, 6.26 and6.66μ, Rf value˜0.37 (silica gel; system toluene/ethyl acetate, 1:1), inthe ratio of 8:1.

The material can be processed further as follows:

7β-Phenylacetamido-3-methoxy-ceph-2-em-4α-carboxylic acid diphenylmethylester can be converted, analogously to Example 17c), into7β-phenylacetamido-3-methoxy-ceph-3-em-4-carboxylic acid diphenylmethylester 1-oxide of melting point 152°-155° C. (from acetone/diethylether), Rf value 0.31 (silica gel; system: ethyl acetate), UV spectrum(in 95% strength ethanol): λ_(max) =288 mμ (ε=3,610) and shoulder atλ=247 mμ; IR spectrum (methylene chloride): characteristic bands at2.94, 5.59, 5.81, 5.95, 6.22 and 6.61μ.

A purer product, which consists mainly of7β-phenylacetamido-3-methoxy-ceph-3-em-4-carboxylic acid diphenylmethylester 1β-oxide, can be obtained as follows:

A solution of 6.7 g (10 mmols) of2-[4-(p-toluenesulphonylthio)-3-phenylacetamido-2-oxoazetidin-1-yl]-3-methoxyisocrotonicacid diphenylmethyl ester in 67 ml of absolute tetrahydrofurane isstirred with 2.28 ml (15 mmols) of 1,5-diazabicyclo[5.4.0]undec-5-enefor 15 minutes at 20° C., 0.7 ml of glacial acetic acid is added and themixture is then concentrated by evaporation in vacuo. The oily, darkresidue is dissolved in 30 ml of methylene chloride and the solution issuccessively extracted by shaking with 15 ml of water, 10 ml of 0.5 Nhydrochloric acid, 10 ml of saturated aqueous sodium bicarbonatesolution and 10 ml of water. The aqueous phases are re-extracted with 10ml of methylene chloride and the organic extracts are combined andstirred with 2.24 ml of 40% strength peracetic acid for 15 minutes at 0°C. in an icebath. A solution of 1.50 g (6 mmols) of sodium thiosulphatepentahydrate in 20 ml of water is then added to the reaction mixture,the whole is stirred for 10 minutes and the aqueous phase is separatedoff. The organic phase is additionally washed with 10 ml of water, driedover sodium sulphate and concentrated by evaporation in vacuo.Crystallisation of the solid residue from methylene chloride/petroleumether gives 7β-phenylacetamido-3-methoxy-ceph-3-em-4-carboxylic aciddiphenylmethyl ester 1β-oxide of melting point 175°-176° C.; thin layerchromatogram (silica gel): Rf value˜0.1 (toluene/ethyl acetate, 1:1), UVspectrum (ethanol): λ_(max) =279 mμ (ε=7,300); IR spectrum (methylenechloride): characteristic bands at 2.94; 5.56; 5.78; 5.91; 6.20 and6.67μ.

7β-Phenylacetamido-3-methoxy-ceph-3-em-carboxylic acid diphenylmethylester can be obtained from the 1-oxides analogously to Example 17e).

From this ester, crude7β-phenylacetamido-3-methoxy-ceph-3-em-4-carboxylic acid can be obtainedby saponification analogously to Example 17a), and can be purified bychromatography on silica gel (containing 5% of water) using methylenechloride containing 30-50% of acetone, followed by lyophilisation fromdioxane; UV spectrum (in 95% strength ethanol): λ_(max) =265 mμ(ε=5,800); IR spectrum (methylene chloride): characteristic bands at3.03, 5.60, 5.74, 5.92, 6.24 and 6.67μ.

The starting material and the intermediate products can be prepared asfollows:

(a) 19.4 ml of 40 percent strength peracetic acid are added over thecourse of 40 minutes to a mixture of 37.24 g (0.1 mol) of the potassiumsalt of penicillin G in 90 ml of water, 7.3 ml of acetone and 150 ml ofchloroform whilst stirring at 0° C. After a further 15 minutes, 28 g(0.15 mol) of benzophenone-hydrazone are added in portions at the sametemperature, followed by 6.3 ml of 1 percent strength aqueous potassiumiodide solution and then followed by a mixture of 32.5 ml of 10 percentstrength sulphuric acid and 28 ml of 40 percent strength peracetic acid,added dropwise over the course of 1.5 hours. After completion of theaddition, the mixture is stirred for a further 30 minutes at 0° C.,warmed to 15° C. and diluted with 400 ml of chloroform. The aqueousphase is separated off and the organic phase is successively washed with300 ml of 5 percent strength aqueous sodium bisulphite solution, 300 mlof saturated aqueous sodium bicarbonate solution and 300 ml of saturatedaqueous sodium chloride solution, dried over sodium sulphate andconcentrated by evaporation in vacuo. The evaporation residue isrecrystallised from ethyl acetate/petroleum ether and gives6-phenylacetamidopenicillanic acid diphenylmethyl ester 1β-oxide,melting point 139° C.; thin layer chromatogram (silica gel): Rfvalue˜0.40 (system toluene/ethyl acetate, 1:1), IR spectrum (methylenechloride): characteristic bands at 2.94, 5.56, 5.70, 5.92 and 6.57μ.

(b) 1.83 g (11 mmols) of 2-mercaptobenzthiazole are added to a mixtureof 5.165 g (10 mmols) of 6-phenylacetamidopenicillanic aciddiphenylmethyl ester 1β-oxide in 50 ml of toluene and 0.5 ml of glacialacetic acid and the mixture is boiled for 2 hours in a reflux apparatusprovided with a water separator. On cooling,2-[4-(benzthiazol-2-yldithio)-3-phenylacetamido-2-oxoazetidin-1-yl]-3-methylene-butyricacid diphenylmethyl ester crystallises out spontaneously. Afterrecrystallising it once from methylene chloride/diethyl ether, crystalsof melting point 134°-136° C. are obtained; thin layer chromatogram(silica gel): Rf value˜0.52 (system toluene/ethyl acetate, 1:1), UVspectrum (ethanol): λ_(max) =269 mμ (ε=12,700); IR spectrum (methylenechloride): characteristic bands at 2.90, 5.60, 5.72, 5.92 and 6.61μ.

(c) The product obtained under (b) does not have to be isolated forfurther conversion. After cooling, the reaction mixture can be diluteddirectly with 30 ml of toluene, after which it is mixed with 3.95 g (15mmols) of silver p-toluenesulphinate and stirred for 2 hours at roomtemperature. The yellow precipitate which has separated out is filteredoff through Hyflo and rinsed with toluene. The filtrate is extracted byshaking with saturated aqueous sodium chloride solution, dried oversodium sulphate and concentrated by evaporation in vacuo. Theevaporation residue is taken up in toluene and petroleum ether is added.The precipitate is filtered off and recrystallised from ethylacetate/petroleum ether. The resulting2-[4-(p-toluenesulphonylthio)-3-phenylacetamido-2-oxoazetidin-1-yl]-3-methylene-butyricacid diphenylmethyl ester has a melting point of 75° C.; thin layerchromatogram (silica gel): Rf value˜0.47 (system toluene/ethyl acetate,1:1), UV spectrum (ethanol): λ_(max) =259 mμ (ε=4,300); IR spectrum(methylene chloride): characteristic bands at 2.92, 5.62, 5.74, 5.94 and6.63μ.

(d) A solution of 655 mg (1 mM) of2-[4-(toluenesulphonylthio)-3-phenylacetamido-2-oxoazetidin-1-yl]-3-methylene-butyricacid diphenylmethyl ester in 65 ml of methylene chloride is treated withan ozone/oxygen mixture at -65° C. until a slight blue colourationresults. After addition of 0.5 ml of dimethyl sulphide, the mixture isallowed to warm up to room temperature and is then concentrated byevaporation in vacuo. The resulting crude2-[4-(p-toluenesulphonylthio)-3-phenylacetamido-2-oxoazetidin-1-yl]-3-hydroxy-crotonicacid diphenylmethyl ester, Rf value˜0.46 (silica gel; systemtoluene/ethyl acetate, 1:1), IR spectrum (methylene chloride):characteristic bands at 2.95, 5.60, 5.98, 6.18 and 6.61μ, can beconverted further without additional purification.

(e) The crude product obtained under (d) is dissolved in 20 ml ofmethanol and a solution of diazomethane in ether is added at 0° C. untila yellow colouration persists. After evaporating off the solvent invacuo, the residue is purified be preparative thick layer chromatographyon silica gel, using toluene/ethyl acetate, 1:1, as the running agent.2-[4-(p-Toluenesulphonylthio)-3-phenylacetamido-2-oxoazetidin-1-yl]-3-methoxy-crotonicacid diphenylmethyl ester, Rf value˜0.2 (silica gel; systemtoluene/ethyl acetate, 1:1), IR spectrum (methylene chloride):characteristic bands at 2.94, 5.61, 5.96, 6.24 and 6.62μ, is obtainedalongside a little2-[4-(p-toluenesulphonylthio)-3-phenylacetamido-2-oxoazetidin-1-yl]-3-methoxy-isocrotonicacid diphenylmethyl ester.

EXAMPLE 19

5.20 ml (35 mmols) of 1,5-diazabicyclo[5.4.0]undec-5-ene are added to asolution of 6.06 g (10 mmols) of a 3:1 mixture of the isomeric2-[4-(p-toluenesulphonylthio)-3-phenoxyacetamido-2-oxoazetidin-1-yl]-3-methoxy-crotonicacid benzyl ester and2-[4-(p-toluenesulphonylthio)-3-phenoxyacetamido-2-oxoazetidin-1-yl]-3-methoxy-isocrotonicacid benzyl ester and 2.33 g (15 mmols) of p-toluenesulphinc acid in 200ml of absolute tetrahydrofurane at room temperature, whilst stirring.The mixture is stirred for a further 40 minutes at room temperature,mixed with 500 ml of methylene chloride and washed successively with 200ml of 0.5 N hydrochloric acid, 200 ml of water, 200 ml of 0.5 N sodiumbicarbonate and 200 ml of water. The methylene chloride phase is driedover sodium sulphate and concentrated by evaporation in vacuo. Theresidue is chromatographed on 200 g of acid-washed silica gel, usingtoluene/ethyl acetate, 3:1, and7β-phenoxyacetamido-3-methoxy-ceph-2-em-4α-carboxylic acid benzyl esterof melting point 148°-151° C. is obtained by adding diethyl ether to thefractions. IR spectrum (methylene chloride): characteristic bands at5.60, 5.75, 5.90, and 8.25μ; [α]_(D) ²⁰ =+284°±1° (c=1; chloroform).

Toluene/ethyl acetate, 2:1, elutes7β-phenoxyacetamido-3-methoxy-ceph-3-em-4-carboxylic acid benzyl ester,which can also be precipitated with diethyl ether, and has a meltingpoint of 89°-91° C.; IR spectrum (methylene chloride): characteristicbands at 5.60, 5.85 and 5.90; [α]_(D) ²⁰ =+47°±1° (c=1; chloroform).

The ratio of the ceph-2-em compound to the ceph-3-em compound is about3:1.

The compounds can be further converted as follows:

15 ml of pre-cooled 0.1 N potassium hydroxide solution are added, whilststirring, to a solution prepared at 0° C., of 454 mg (1 mmol) of anapprox. 3:1 mixture of7β-phenoxyacetamido-3-methoxy-ceph-2-em-4α-carboxylic acid benzyl esterand 7β-phenoxyacetamido-3-methoxy-ceph-3-em-4-carboxylic acid benzylester in 30 ml of tetrahydrofurane. The mixture is stirred for a further5 minutes at 0° C., 100 ml of ice water and 100 ml of pre-cooledmethylene chloride are then added and the whole is stirred vigorously.Addition of a little saturated aqueous sodium chloride solution causesthe mixture to separate into two phases. The methylene chloride phase isseparated off and the aqueous phase is washed with a further 30 ml ofmethylene chloride. The aqueous phase is covered with 50 ml of methylenechloride, 10 ml of 2 N hydrochloric acid are added and the mixture isthoroughly shaken. After separating off the organic phase, the aqueousphase is extracted twice more with 30 ml of methylene chloride at atime. The combined methylene chloride extracts are dried over sodiumsulphate and concentrated by evaporation in vacuo. The resulting whitefoam crystallises on addition of chlorofrom and diethyl ether and gives7β-phenoxyacetamido-3-methoxy-ceph-2-em-4α-carboxylic acid of meltingpoint 142° C. (decomposition). IR spectrum (KBr): characteristic bandsat 5.65, 5.75 and 5.95μ.

The starting material can be prepared as follows:

(a) 20 ml (14.6 g, 0.145 mol) of triethylamine and 17 ml (24.5 g, 0.143mol) of benzyl bromide are added to a solution of 36.6 g (0.1 mol) of6-phenoxyacetamido-penicillanic acid 1β-oxide in 150 ml of drydimethylformamide whilst cooling with tap water. The mixture is stirredfor 20 hours at room temperature and is then poured onto ice water. Theprecipitate is filtered off, washed with approx. 1,000 ml of water,dried for 2 days in vacuo at 40° C., then taken up in 200 ml ofmethylene chloride and again dried with sodium sulphate. The white foamwhich remains after evaporating off the solvent in vacuo is dissolved in150 ml of ethyl acetate and the solution is left to stand first at roomtemperature and then at -20° C., whereupon pure6-phenoxyacetamido-penicillanic acid benzyl ester 1β-oxide crystallises.Melting point 139°-140° C.; IR spectrum (methylene chloride);characteristic bands at 5.55, 5.75 and 5.90μ; [α]_(D) ²⁰ =+174°±1° (c=1,chloroform).

Further quantities of the crystalline benzyl ester 1β-oxide can beobtained from the mother liquor by chromatography on 250 g ofacid-washed silica gel, using toluene/ethyl acetate (1:1).

(b) 4.56 g (10 mmols) of 6-phenoxyacetamido-penicillanic acid benzylester 1β-oxide and 1.84 g (11 mmols) of 2-mercaptobenzthiazole in 100 mlof toluene are heated for 5 hours under reflux (bath temperature 135°C.). The mixture is left to stand, whereupon2-[4-(benzthiazol-2-yldithio)-3-phenoxyacetamido-2-oxoazetidin-1-yl]-3-methylene-butyricacid benzyl ester crystallises out. The crystals are filtered off,washed with 50 ml of toluene and dried in a high vacuum. Furtherquantities of the crystalline product can be obtained by chromatographyof the mother liquor on 70 g of acid-washed silica gel, usingtoluene/ethyl acetate (3:1). Melting point of the pure product 150°˜153°C.; IR spectrum (methylene chloride): characteristic bands at 5.60, 5.75and 5.90μ; [α]_(D) ²⁰ =-112°±1° (c=1; chloroform).

(c) An oxygen/ozone mixture is passed through a solution of 6.06 g (10mmols) of2-[4-(benzthiazol-2-yldithio)-3-phenoxy-acetamido-2-oxoazetidin-1-yl]-3-methylene-butyricacid benzyl ester in 300 ml of methylene chloride at -20° C. until thestarting material has been completely ozonised (as checked by means ofthin layer chromatography on silica gel, using toluene/ethyl acetate,1:1). 50 ml of 10% strength aqueous sodium bisulphite solution are thenadded to the mixture which is stirred until (after 5 minutes) ozonide isno longer detectable with potassium iodide/starch. 300 ml of water areadded to the mixture and the product is partitioned between the twophases produced. The organic phase is dried over sodium sulphate andfreed from the solvent. The residue is triturated in 100 ml ofether-pentane (1:1) at 0° C., whereupon2-[4-(benzthiazol-2-yldithio)-3-phenoxyacetamido-2-oxoazetidin-1-yl]-3-hydroxy-crotonicacid benzyl ester melting point 58°-62° C., crystallises out; IRspectrum (methylene chloride): characteristic bands at 5.60, 5.90 and6.00μ; [α]_(D) ²⁰ =-92°±1° (c=1, chloroform).

(d) 6.08 g (0.01 mol) of2-[4-(benzthiazol-2-yldithio)-3-phenoxyacetamido-2-oxoazetidin-1-yl]-3-hydroxy-crotonicacid benzyl ester and 3.50 g (0.013 mol) of silver p-toluenesulphinateare stirred in 200 ml of acetone-water (9:1) for 60 minutes at roomtemperature. The yellow precipitate formed is filtered off throughCellit, the residue is washed with acetone and the filtrate isconcentrated in vacuo to a volume of approx. 20 ml. The product is thenpartitioned between methylene chloride and dilute aqueous sodiumsulphate solution. The organic phase is dried over sodium sulphate andthe solvent is evaporated in vacuo. The residue is taken up in 70 ml ofethyl acetate, if necessary with warming, freed from a little insolublematter by filtration and again concentrated by evaporation. On additionof 100 ml of ether-pentane at 0° C.,2-[4-(p-toluenesulphonylthio)-3-phenoxyacetamido-2-oxoazetidin-1-yl]-3-hydroxy-crotonicacid benzyl ester of melting point 151°-152° C. crystallises out; IRspectrum (methylene chloride): characteristic bands at 5.60, 5.90, 6.00and 8.75μ; [α]_(D) ²⁰ =-16°±1° (c=1; chloroform).

(e) A solution of diazomethane in ether is added dropwise to a solutionof 5.97 g (0.01 mol) of pure2-[4-(p-toluene-sulphonylthio)-3-phenoxyacetamido-2-oxoazetidin-1-yl]-3-hydroxy-crotonicacid benzyl ester in 50 ml of methylene chloride at 0° C., whilststirring, until the starting material has been completely methylated(checked by thin layer chromatography on silica gel, using toluene/ethylacetate, 1:1). Excess diazomethane is neutralised by a few drops ofglacial acetic acid (but an excess of glacial acetic acid should beavoided), after which the mixture is concentrated by evaporation invacuo. The yellowish, foam-like residue is crystallised from diethylether/pentane (1:1), giving an isomer mixture consisting of2-[4-(p-toluenesulphonylthio)-3-phenoxyacetamido-2-oxoazetidin-1-yl]-3-methoxy-crotonicacid benzyl ester and2-[4-(p-toluene-sulphonylthio)-3-phenoxyacetamido-2-oxoazetidin-1-yl]-3-methoxy-isocrotonicacid benzyl ester in the ratio of about 3:1.

The two isomers can be separated by repeated chromatography on silicagel, using toluene/ethyl acetate, 1:1. The resulting2-[4-(p-toluenesulphonylthio)-3-phenoxyacetamido-2-oxoazetidin-1-yl]-3-methoxy-crotonicacid benzyl ester has a melting point of 166°-168° C.; [α]_(D) ²⁰=-36°±1° (c=1; chloroform); IR spectrum (methylene chloride):characteristic bands at 5.60, 5.80, 5.90 and 8.72μ; NMR spectrum(chloroform): characteristic bands at 2.12 (s); 5.00 (dd); 5.90 (d) ppm;thin layer chromatogram: Rf value˜0.10 (silica gel; toluene/ethylacetate, 1:1). The resulting2-[4-(p-toluenesulphonylthio)-3-phenoxyacetamido-2-oxoazetidin-1-yl]-3-methoxy-isocrotonicacid benzyl ester has a melting point of 59°-63° C.; [α]_(D) ²⁰ =-1°±1°(c=1; chloroform); IR spectrum (methylene chloride): characteristicbands at 5.60, 5.87 sh. 5.90 and 8.72μ; NMR spectrum (chloroform):characteristic bands at 3.23 (s), 5.45 (d,d), 5.73 (d) ppm; thin layerchromatogram: Rf value˜0.13 (silica gel; toluene/ethyl acetate, 1:1).

EXAMPLE 20

302 mg (2 mmols) of 1,5-diazabicyclo[5.4.0]undec-5-ene are added to asolution of 534 mg (1 mmol) of a mixture consisting of2-[4-(p-toluenesulphonylthio)-3-phenoxyacetamido-2-oxoazetidin-1-yl]-3-methoxy-isocrotonicacid methyl ester and2-[4-(p-toluenesulphonylthio)-3-phenoxyacetamido-2-oxoazetidin-1-yl]-3-methoxy-crotonicacid methyl ester in the ratio of about 4:1, in 20 ml oftetrahydrofurane, whilst stirring. The mixture is then stirred for 40minutes, diluted with 70 ml of methylene chloride and washedsuccessively with dilute hydrochloric acid, with water, with diluteaqueous sodium bicarbonate solution and again with water. The organicphase is dried over sodium sulphate and concentrated by evaporation invacuo. The residue is chromatographed on 15 g of acid-washed silica gelusing toluene/ethyl acetate, 2:1 followed by 1:1, resulting in theelution of, first, pure7β-phenoxyacetamido-3-methoxy-ceph-2-em-4α-carboxylic acid methyl ester,IR spectrum (in methylene chloride): characteristic bands at 5.60, 5.70,5.90 and 8.25μ, followed by pure7β-phenoxyacetamido-3-methoxy-ceph-3-em-4-carboxylic acid methyl ester,IR spectrum (in methylene chloride): characteristic bands at 5.60, 5.85,5.90 and 7.10μ, in the form of colourless foams.

The compounds obtained can be further converted as follows:

15 ml of cooled 0.1 N aqueous potassium hydroxide solution are added,whilst stirring, to a solution, cooled in an ice bath, of 382 mg of7β-phenoxyacetamido-3-methoxy-ceph-2-em-4α-carboxylic acid methyl esterin 30 ml of tetrahydrofurane. After 5 minutes, 100 ml of water and 70 mlof methylene chloride are added and the mixture is acidified by adding10 ml of 1 N aqueous hydrochloric acid. The methylene chloride phase isseparated off and the aqueous phase is extracted with 30 ml of methylenechloride. The combined organic phases are dried over sodium sulphate andconcentrated by evaporation in vacuo. The residue is crystallised fromchloroform/diethyl ether and gives7β-phenoxyacetamido-3-methoxy-ceph-2-em-4α-carboxylic acid of meltingpoint 142° C. (decomposition).

The same compound, of melting point 142° C. (decomposition) is obtainedwhen 7β-phenoxyacetamido-3-methoxy-ceph-3-em-4-carboxylic acid methylester is saponified with 0.1 N potassium hydroxide solution, asdescribed earlier.

The starting materials can be prepared as follows:

(a) A solution of 19.25 g (50 mmols) of 6-phenoxyacetamido-penicillanicacid methyl ester 1β-oxide and 9.4 g (55 mmols) of2-mercaptobenzthiazole in 500 ml of dry toluene is boiled for 8 hoursunder reflux and then concentrated in vacuo. The residue is dissolved in400 ml of ethyl acetate whilst warming (˜80° C.). and the solution istreated with 0.2 g of active charcoal and filtered through anelectrically heated glass frit. On cooling,2-[4-(benzthiazol-2-yldithio)-3-phenoxyacetamido-2-oxoazetidin-1-yl]-3-methylene-butyricacid methyl ester of melting point 132°˜134° C. separates out. Furtherquantities of this compound (melting point 135°˜137° C.) can be obtainedfrom the mother liquors.

(b) An ozone/oxygen mixture is passed through a solution of 20.6 g (40mmols) of2-[4-(benzthiazol-2-yldithio)-3-phenoxyacetamido-2-oxoazetidin-1-yl]-3-methylene-butyricacid methyl ester in 400 ml of acetone at -20° C. until no furtherstarting material is detectable by thin layer chromatography (silicagel, toluene/ethyl acetate, 1:1). 40 ml of dimethylsulphide are thenadded to the mixture and the whole is stirred for 3 days at roomtemperature until ozone is no longer detectable with potassiumiodide/starch. The mixture is concentrated by evaporation in vacuo andthe liquid residue is poured onto 400 ml of ice water. The precipitateis filtered off, washed with 200 ml of ice water, dried in vacuo andcrystallised from diethyl ether/pentane at 0° C. The resulting2-[4-(benzthiazol-2-yldithio)-3-phenoxyacetamido-2-oxoazetidin-1-yl]-3-hydroxycrotonicacid methyl ester has a melting point of 127°˜130° C.; IR spectrum (inmethylene chloride): characteristic bands at 5.60, 5.90, 6.00 and 8.10μ.Further quantities of the product can be obtained by chromatography ofthe mother liquors on silica gel, using toluene/ethyl acetate, 3:1.

(c) Sufficient of a solution of diazomethane in ether is added to asolution of 4.85 g (0.01 mol) of2-[4-(benzthiazol-2-yldithio)-3-phenoxyacetamido-2-oxoazetidin-1-yl]-3-hydroxycrotonicacid methyl ester in 50 ml of methylene chloride at 0° C., whilststirring, that after periods of stirring of 15 minutes starting materialis in each case no longer detectable by thin layer chromatography(silica gel, toluene/ethyl acetate, 1:1). Excess diazomethane isneutralised with a minimum amount of acetic acid and the mixture isconcentrated by evaporation in vacuo. The residue consists of a mixtureof2-[4-(benzthiazol-2-yldithio)-3-phenoxyacetamido-2-oxoazetidin-1-yl]-3-methoxy-isocrotonicacid methyl ester and2-[4-(benzthiazol-2-yldithio)-3-phenoxyacetamido-2-oxoazetidin-1-yl]-3-methoxy-crotonicacid methyl ester in the ratio of about 4:1. IR spectrum (in methylenechloride): characteristic bands at 5.60, 5.85, 5.90, 9.05 and 10.00μ.

(d) A mixture comprising 5.03 g (0.01 mol) of a mixture of2-[4-(benzthiazol-2-yldithio)-3-phenoxyacetamido-2-oxoazetidin-1-yl]-3-methoxy-isocrotonicacid methyl ester and the corresponding crotonic acid methyl ester inthe ratio of about 4:1, 3.50 g (0.013 mol) of silver p-toluenesulphinateand 200 ml of acetone/water, 9:1, is stirred for 40 minutes at roomtemperature and then filtered through Cellit. The filter residue iswashed with acetone and the combined filtrates are concentrated in vacuoto a volume of about 20 ml. After adding 100 ml of methylene chlorideand 100 ml of dilute aqueous sodium sulphate solution, the whole isshaken thoroughly, the aqueous phase is separated off and the methylenechloride phase is dried over sodium sulphate and concentrated byevaporation in vacuo. The residue is purified by trituration withdiethyl ether/pentane at 0° C. and is filtered off. A mixture of2-[4-(p-toluenesulphonylthio)-3-phenoxyacetamido-2-oxoazetidin-1-yl]-3-methoxy-isocrotonicacid methyl ester and2-[4-(p-toluenesulphonylthio)-3-phenoxyacetamido-2-oxoazetidin-1-yl]-3-methoxy-crotonicacid methyl ester in the ratio of about 4:1 is obtained in the form of awhite powder. IR spectrum (in methylene chloride) characteristic bandsat 5.60, 5.85, 5.90 and 8.75μ.

EXAMPLE 21

A solution of 731 mg (1 mmol) of a 1:1 mixture consisting of2-[4-(p-toluenesulphonylthio)-3-phenoxyacetamido-2-oxoazetidin-1-yl]-3-benzoxy-crotonicacid p-nitrobenzyl ester and the corresponding isocrotonic acidp-nitrobenzyl ester in a mixture of 0.185 ml (1.2 mmols) of1,5-diazabicyclo[5.4.0]undec-5-ene in 20 ml of dry tetrahydrofurane isstirred for precisely 35 minutes at room temperature. 50 ml of methylenechloride are added to the mixture and the whole is washed successivelywith dilute hydrochloric acid, water and dilute aqueous sodiumbicarbonate solution. The organic phase is dried over sodium sulphateand concentrated by evaporation in vacuo. The residue is chromatographedon 25 mg of acid-washed silica gel, using toluene/ethyl acetate (3:1). Amixture consisting of the ceph-2-em compound and the ceph-3-em compoundin the ratio of about 3:1 is obtained; this mixture can be separated byrepeated chromatography into the pure isomers, giving7β-phenoxyacetamido-3-benzoxy-ceph-2-em-4α-carboxylic acid p-nitrobenzylester of melting point 160° C.-162° C. (diethyl ether/pentane); IRspectrum (methylene chloride), characteristic bands at 5.6, 5.7, 5.9 and7.4μ, and 7β-phenoxyacetamido-3-benzoxy-ceph-3-em-4-carboxylic acidp-nitrobenzyl ester in the form of a colourless foam, IR spectrum(methylene chloride): characteristic bands at 5.6, 5.8 sh, 5.9, 7.9 and8.4μ.

The isomer mixture obtained can be further converted as follows:

The isomer mixture obtained, consisting of7β-phenoxyacetamido-3-benzoxy-ceph-2-em-4α-carboxylic acid p-nitrobenzylester and 7β-phenoxyacetamido-3-benzoxy-ceph-3-em-4-carboxylic acidp-nitrobenzyl ester in the ratio of about 3:1, is dissolved in 8 ml oftrifluoroacetic acid and the solution is stirred for 90 minutes at roomtemperature. The reaction mixture is then concentrated by evaporation invacuo and residual trifluoroacetic acid is repeatedly driven off withtoluene. The residue is chromatographed on 20 g of acid-washed silicagel, using toluene/ethyl acetate (3:1), giving7β-phenoxyacetamido-3-hydroxy-ceph-3-em-4-carboxylic acid p-nitrobenzylester in the form of a colourless foam. IR spectrum (methylenechloride): characteristic bands at 2.95, 3.3, 5.6, 5.75 sh, 5.9, 5.95sh, 6.55, 7.45, 8.15 and 8.3μ; NMR spectrum (deuterochloroform):characteristic bands at 3.4 (2H, AB q, J=17 Hz), 4.57 (2H, s), 5.06 (1H,d, J=5 Hz), 5.35 (2H, AB q, J=14 Hz), 5.7 (1H, dd, J=5, 10 Hz), 6.8-8.4(10H, c), 11.4 (1H, br.s.) ppm.

The starting material can be prepared as follows:

30 ml of the solution prepared "in situ" (fromN-benzyl-N-nitrotoluenesulphonamide, of 1.2 g (approx. 10 mmols) ofphenyldiazomethane in ether is added, at room temperature, to a solutionof 1.282 g (2 mmols) of2-[4-(p-toluenesulphonyl-thio)-3-phenoxyacetamido-2-oxoazetidin-1-yl]-3-hydroxy-crotonicacid p-nitrobenzyl ester in 4 ml of distilled dioxane. The mixture isboiled for 6 hours under reflux at 45° C. bath temperature, diluted with100 ml of methylene chloride and then washed with 100 ml of water. Theorganic phase is dried over sodium sulphate, concentrated by evaporationin vacuo and dried in a high vacuum. The resulting yellow oil ischromatographed on 100 g of acid-washed silica gel, using toluene/ethylacetate, 3:1 and 2:1, as the running agents. An isomer mixtureconsisting of2-[4-(p-toluenesulphonylthio)-3-phenoxyacetamido-2-oxoazetidin-1-yl]-3-benzoxy-crotonicacid p-nitrobenzyl ester and2-[4-(p-toluenesulphonylthio)-3-phenoxyacetamido-2-oxoazetidin-1-yl]-3-benzoxy-isocrotonicacid p-nitrobenzyl ester in the ratio of about 1:1 is obtained; this canbe separated into the individual isomers by repeated chromatography, asdescribed earlier. IR spectrum of the faster-running crotonic acidderivative (methylene chloride): characteristic bands at 5.6, 5.80, 5.90and 8.75μ; NMR spectrum (deuterochloroform): characteristic bands at 2.2(s), 5.05 (dd), 5.93 (d) ppm; thin layer chromatogram: Rf value˜0.3(silica gel; toluene/ethyl acetate,2:1); IR spectrum of theslower-running isocrotonic acid derivative (methylene chloride):characteristic bands at 5.6, 5.85 sh, 5.90 and 8.75μ; NMR spectrum(deuterochloroform): characteristic bands at 2.5 (s), 5.41 (dd), 5.77(d) ppm; thin layer chromatogram: Rf value˜0.25 (silica gel;toluene/ethyl acetate, 2:1).

EXAMPLE 22

405 mg (0.5 mmol) of an isomer mixture consisting of2-[4-(p-toluenesulphonylthio)-3-phenoxyacetamido-2-oxoazetidin-1-yl]3-diphenylmethoxy-crotonicacid p-nitrobenzyl ester and the corresponding isomeric isocrotonic acidester are dissolved in 8 ml of dry tetrahydrofurane containing 0.9 ml(0.6 mmol) of 1,5-diazabicyclo[5.4.0]undec-1-ene and the solution isstirred for precisely 45 minutes at room temperature. The yellowreaction mixture is then diluted with 25 ml of methylene chloride andwashed with 0.5 N hydrochloric acid, water and dilute aqueous sodiumbicarbonate solution. The organic phase is dried over sodium sulphateand concentrated by evaporation.

An isomer mixture consisting of7β-phenoxyacetamido-3-diphenylmethoxy-ceph-2-em-4α-carboxylic acidp-nitrobenzyl ester and7β-phenoxyacetamido-3-diphenylmethoxy-ceph-3-em-4-carboxylic acidp-nitrobenzyl ester is obtained; IR spectrum (methylene chloride):characteristic bands at 5.60, 5.70, 5.90, 6.55 and 7.40μ.

The resulting isomer mixture of the two compounds can be furtherconverted as follows:

A solution of 340 mg of the resulting isomer mixture, consisting of7β-phenoxyacetamido-3-diphenylmethoxy-ceph-2-em-4α-carboxylic acidp-nitrobenzyl ester and7β-phenoxyacetamido-3-diphenylmethoxy-ceph-3-em-4-carboxylic acidp-nitrobenzyl ester, in a mixture of 0.5 ml of trifluoroacetic acid and9.5 ml of methylene chloride is stirred for 40 minutes at roomtemperature. The mixture is concentrated by evaporation in vacuo,toluene is added to the residue, and the mixture is again concentratedby evaporation. The resulting residue (which still containstrifluoroacetic acid) is chromatographed on 15 g of acid-washed silicagel, using toluene/ethyl acetate (3:1), whereby7β-phenoxyacetamido-3-hydroxy-ceph-3-em-4-carboxylic acid p-nitrobenzylester is obtained; IR spectrum (methylene chloride): characteristicbands at 2.95, 3,3, 5.6, 5.75 sh, 5.9, 5.95 sh, 6.55, 7.45, 8.15 and8.3μ; NMR spectrum (deuterochloroform): characteristic bands at 3.4 (2H,AB q, l=17 Hz), 4.57 (2H, s), 5.06 (1H, d,l=5 Hz), 5.35 (2H, AB q, l=14Hz), 5.7 (1H, dd, l=5, 10 Hz), 6.8-8.4 (10 H, c), 11.4 (1H, br. s.) ppm.

The starting material can be obtained as follows:

A solution of 350 mg (1.75 mmols) of diphenyldiazomethane in 0.3 ml ofdioxane is added to a solution of 641 mg (1 mmol) of2-[4-(p-toluenesulphonylthio)-3-phenoxyacetamido-2-oxoazetidin-1-ly]-3-hydroxy-crotonicacid p-nitrobenzyl ester in 0.5 ml of distilled dioxane and the reactionmixture is warmed to 50° C. for 36 hours, without stirring. The mixtureis concentrated by evaporation in vacuo, the dioxane which remains isdriven off by adding toluene and again concentrating by evaporation, andthe residue is chromatographed on 20 g of acid-washed silica gel, usingtoluene/ethyl acetate (7:1) and (3:1)

An isomer mixture consisting of2-[4-(p-toluenesulphonylthio)-3-phenoxyacetamido-2-oxoazetidin-1-yl]-3-diphenylmethoxy-crotonicacid p-nitrobenzyl ester and2-[4-(p-toluenesulphonylthio)-3-phenoxyacetamido-2-oxoazetidin-1-ly]-3-diphenylmethoxy-isocrotonicacid p-nitrobenzyl ether is obtained, IR spectrum (methylene chloride):characteristic bands at 5.6, 5.85 sh, 5.9, 6.25, 6.55, 7.43 and 8.75μ.

EXAMPLE 23

800 mg (5.25 mmols) of 1,5-diazabicyclo[5.4.0]undec-5-ene are added to asolution of 933 mg (1.5 mmols) of an isomer mixture consisting of2-[4-(benzthiazol-2-yldithio)-3-phenoxyacetamido-2-oxoazetidin-1yl]-3-benzoxy-crotonicacid methyl ester and the corresponding isocrotonic acid methyl ester,in the ratio of about 1:1, and 350 mg (2.25 mmols) of p-toluenesulphinicacid in 30 ml of dry tetrahydrofurane, and the reaction mixture isstirred for precisely 40 minutes at room temperature. It is then dilutedwith 100 ml of benzene and washed with dilute aqueous hydrochloric acid,with water, with dilute aqueous sodium hydroxide solution and again withwater. The benzene phase is dried over sodium sulphate and concentratedby evaporation in vacuo. Chromatography using toluene/ethyl acetate(5:1) on silica gel gives an isomer mixture consisting of7β-phenoxyacetamido-3-benzoxy-ceph-3-em-4-carboxylic acid methyl esterand 7β-phenoxyacetamido-3-benzoxy-ceph-2-em-4-carboxylic acid methylester: IR spectrum (methylene chloride): characteristic bands at 5.60,5.72, 5.85 sh and 5.90μ.

The starting material can be prepared as follows:

960 mg (approx. 8 mmols) of freshly distilled phenyldiazomethane areadded to a solution of 483 mg (1 mmol) of2-[4-benzthiazol-2-yldithio)-3-phenoxyacetamido-2-oxoazetidin-1-yl]-3-hydroxy-crotonicacid methyl ester in 1.5 ml of methylene chloride/diethyl ether and thereaction mixture is stirred for 20 hours at 0° C., then diluted withmethylene chloride and washed with water. The organic phase is driedover sodium sulphate and concentrated by evaporation in vacuo. Theresidue is dried in a high vacuum and then chromatographed on 10 g ofacid-washed silica gel, using toluene/ethyl acetate (2:1), giving anisomer mixture consisting of2-[4-(benzthiazol-2-yldithio)-3-phenoxyacetamido-2-oxoazetidin-1-yl]-3-benzoxycrotonicacid methyl ester and the corresponding isocrotonic acid methyl ester inthe ratio of about 1:1; IR spectrum (methylene chloride): characteristicbands at 5.6, 5.85 sh, 5.9 and 9.9μ.

EXAMPLE 24

Analogously to Example 5 d, reaction of 1.16 g (3 mmols) of7β-amino-3-methoxy-ceph-3-em-4-carboxylic acid hydrochloride dioxanate,obtainable according to the invention, with 1.5 ml (6.2 mmols) ofbis-(trimethylsilyl)-acetamide and subsequently with

(a) 765 mg (3.6 mmols) of D-α-amino-(2-thienyl)-acetyl chloridehydrochloride give7β-[D-α-amino-α-(2-thienyl)-acetylamino]-3-methoxy-3-cephem-4-carboxylicacid in the form of the inner salt, melting point 140° C. (withdecomposition); thin layer chromatogram (silica gel; identification withiodine): Rf˜0.22 (system: n-butanol/acetic acid/water, 67:10:23) andRf˜0.53 (system: isopropanol/formic acid/water, 77:4:19); ultravioletabsorption spectrum: λ_(max) =235 mμ (μ=11,400) and λ_(shoulder) =272 mμ(μ=6,100) in 0.1 N hydrochloric acid, and λ_(max) =238 mμ (μ=11,800) andλ_(shoulder) =267 mμ (ε=6,500) in 0.1 N aqueous sodium bicarbonatesolution.

If a stage (a) is replaced by reaction with

(b) 940 mg (4.5 mmols) of D-α-amino-(1,4-cyclohexadienyl)-acetylchloride hydrochloride,7β-[D-α-amino-α-(1,4-cyclohexadienyl)-acetylamino]-3-methoxy-3-cephem-4-carboxylicacid is obtained in the form of the inner salt, melting point 170° C.(with decomposition); thin layer chromatogram (silica gel;identification with iodine): Rf˜0.19 (system: n-butanol/aceticacid/water, 67:10:23) and Rf˜0.58 (system: isopropanol/formicacid/water, 77:4:19); ultraviolet absorption spectrum: λ_(max) =267 mμ(ε=6,300) in 0.1 N hydrochloric acid, and λ_(max) =268 mμ (ε=6,600) in0.1 N aqueous sodium bicarbonate solution, [α]_(D) ²⁰ =+88°±1° (c=1.06;0.1 N hydrochloric acid).

If stage (a) is replaced by reaction with (c) 800 mg (3.6 mmols) ofD-α-amino-4-hydroxyphenylacetyl chloride hydrochloride,7β-[D-α-amino-α-(4-hydroxyphenyl)-acetylamino]-3-methoxy-3-cephem-4-carboxylicacid is obtained in the form of the inner salt, meltingpoint=243°-244.5° C. (with sintering starting from 231° C. onwards)(with decomposition); thin layer chromatogram (silica gel;identification with iodine): Rf˜0.24 (system: n-butanol/aceticacid/water, 67:10:23) and Rf˜0.57 (system: isopropanol/formicacid/water, 77:4:19); ultraviolet absorption spectrum: λ_(max) =228 mμ(ε=12,000) and 271 mμ (ε=6,900) in 0.1 N hydrochloric acid, and λ_(max)=227 mμ (ε=10,500) and λ_(shoulder) =262 mμ (ε=8,000) in 0.1 N aqueoussodium bicarbonate solution, [α]_(D) ²⁰ =+165°±1° (c=1.3; 0.1 Nhydrochloric acid).

EXAMPLE 25

The following compounds can be prepared analogously from suitableintermediate products obtainable in accordance with the invention:7β-amino-3-methoxy-3-cephem-4-carboxylic acid diphenylmethyl ester orsalts thereof, 3-n-butoxy-7β-phenylacetylamino-3-cephem-4-carboxylicacid diphenylmethyl ester,3-n-butoxy-7β-(D-α-tert.-butoxycarbonylamino-α-phenylacetylamino)-3-cephem-4-carboxylicacid diphenylmethyl ester,3-n-butoxy-7β-(D-α-phenylglycylamino)-3-cephem-4-carboxylic acid orsalts thereof, 3-methoxy-7β-phenylacetylamino-3-cephem-4-carboxylic acidmethyl ester,3-ethoxy-7β-(D-α-tert.-butoxycarbonylamino-α-phenylacetylamino)-3-cephem-4-carboxylicacid diphenylmethyl ester,3-ethoxy-7β-(D-α-phenylglycylamino)-3-cephem-4-carboxylic acid or saltsthereof,3-benzoxy-7β-(D-α-tert.-butoxycarbonylamino-α-phenylacetylamino)-3-cephem-4-carboxylicacid diphenylmethyl ester,3-benzoxy-7β-(D-α-phenylglycylamino)-3-cephem-4-carboxylic acid or saltsthereof,7β-(5-benzoylamino-5-diphenylmethoxycarbonylvalerylamino)-3-methoxy-3-cephem-4-carboxylicacid diphenylmethyl ester,7β-(D-α-tert.-butoxycarbonylamino-α-phenylacetylamino)-3-methoxy-3-cephem-4-carboxylicacid or salts thereof,7β-[D-α-tert.-butoxycarbonylamino-α-(2-thienyl)-acetylamino]-3-methoxy-3-cephem-4-carboxylicacid diphenylmethyl ester,7β-[D-α-tert.-butoxycarbonylamino-α-(1,4-cyclohexadienyl)-acetylamino]-3-methoxy-3-cephem-4-carboxylicacid diphenylmethyl ester,7β-[D-α-amino-α-(1-cyclohexen-1-yl)-acetylamino]-3-methoxy-3-cephem-4-carboxylicacid or salts thereof,7β-[D-α-tert.-butoxycarbonylamino-α-(4-hydroxyphenyl)-acetylamino]-3-methoxy-3-cephem-4-carboxylicacid diphenylmethyl ester,7β-[D-α-tert.-butoxycarbonylamino-α-(4-isothiazolyl)-acetylamino]-3-methoxy-3-cephem-4-carboxylicacid diphenylmethyl ester,7β-(D-α-tert.-butoxycarbonylamino-α-phenylacetylamino)-3-methoxycarbonyloxy-3-cephem-4-carboxylicacid diphenylmethyl ester, as well as the corresponding ceph-2-emcompounds and the isomer mixtures consisting of the ceph-3-em compoundsand the ceph-2-em compounds, and also the 1-oxides of the correspondingceph-3-em compounds.

What we claim is:
 1. Process for the manufacture of a7β-amino-3-cephem-3-ol-4-carboxylic acid compound of the formula##STR9## wherein R₁ ^(a) represents an acyl group of the formula##STR10## wherein R^(I) represents hydrogen or cycloalkyl with 5-7 ringcarbon atoms which is substituted in the 1-position, by amino, protectedamino, sulphoamino or sulphoamino in the form of a salt, or R^(I)represents phenyl, naphthyl or tetrahydronaphthyl, or phenyl, naphthylor tetrahydronaphthyl substituted by hydroxyl, protected hydroxyl,and/or by halogen, a 4-isoxazolyl group or a 4-isoxazolyl groupsubstituted by lower alkyl, and/or phenyl, which can in turn carryhalogen, or R^(I) represents an amino group which is N-substituted bylower alkyl or halogen-substituted lower alkyl, or R₁ represents an acylgroup of the formula ##STR11## wherein R^(I) represents lower alkyl,halogene-lower alkyl, phenyloxy-lower alkyl, hydroxyphenyloxy-loweralkyl, protected hydroxyphenyloxy-lower alkyl, halogeno-phenyloxy-loweralkyl, or lower alkyl substituted by amino and/or carboxyl, whereinamino is free or protected and carboxyl is free or protected, or R^(I)represents lower alkenyl, phenyl, hydroxyphenyl, protectedhydroxyphenyl, halogenophenyl, hydroxy-halogeno-phenyl, protectedhydroxy-halogenophenyl, amino-lower alkyl-phenyl, protected amino-loweralkyl-phenyl, phenyloxyphenyl, or R^(I) represents pyridyl, pyridinium,thienyl, furyl, imidazolyl or tetrazolyl, or these heterocyclic groupssubstituted by lower alkyl, amino, protected amino, aminomethyl orprotected aminomethyl, or R^(I) represents lower alkoxy, phenyloxy,hydroxyphenyloxy, protected hydroxyphenyloxy, halogenophenyloxy, loweralkylthio, lower alkenylthio, phenylthio, pyridylthio, 2-imidazolylthio,1,2,4-triazol-3-ylthio, 1,3,4-triazol-2-ylthio,1,2,4-thiadiazol-3-ylthio, 1,3,4-thiadiazol-2-ylthio, or5-tetrazolythio, and these heterocyclylthio groups, substituted by loweralkyl, or R^(I) represents halogeno, lower alkoxycarbonyl, cyano,carbamoyl, N-lower alkyl-carbamoyl, N-phenylcarbamoyl, lower alkanoyl,benzoyl, or azido, or R₁ ^(a) represents an acyl group of the formula##STR12## wherein R^(I) represents lower alkyl, phenyl, hydroxyphenyl,protected hydroxyphenyl, halogenophenyl, hydroxy-halogenophenyl,protected hydroxy-halogeno-phenyl, furyl, thienyl, or isothiazolyl, andalso represents 1,4-cyclohexadienyl, and R^(II) represents amino,protected amino, guanidinocarbonylamino, sulphoamino, sulphoamino insalt-form, azido, carboxyl, carboxyl in salt-form, protected carboxyl,cyano, sulpho, hydroxyl, protected hydroxyl, O-lower alkyl-phosphono,O,O'-di-lower alkyl-phosphono or halogeno or R₁ ^(a) represents a groupof the formula ##STR13## wherein R^(I) and R^(II) each representhalogen, or lower alkoxycarbonyl, or R₁ ^(a) represents a group of theformula ##STR14## wherein R^(I) represents phenyl, hydroxyphenyl,protected hydrophenyl, hydroxy-halogeno-phenyl, protectedhydrohalogenophenyl, furyl, thienyl, isothiazolyl, or1,4-cyclohexadienyl, and R^(II) represents aminomethyl or protectedaminomethyl or R₁ ^(a) represents a group of the formula ##STR15##wherein each of the groups R^(I), R^(II) and R^(III) represents loweralkyl, and R₁ ^(b) represents hydrogen, or R₁ ^(a) and R₁ ^(b) togetherrepresents 1-oxo-3-aza-1,4-butylen, such group substituted in the2-position by a group R^(I) as defined under formula (A₃) an such groupsubstituted in the 4-position by lower alkyl, R₂ represents a group R₂^(A) which together with the carbonyl grouping --C(═O)-- forms aprotected carboxyl group, a 1-oxide thereof or a metal or an ammoniumsalt of such a compound having a sulpho or a carboxy group or an acidaddition salt of such a compound having a basic amino group,characterised in that in a compound of the formula ##STR16## wherein thedotted line indicates a double bond in the 2,3- or in the 3,4-position,R₁ ^(a), R₁ ^(b) and R₂ have the above mentioned meanings, and R₃ ^(o)is a 2-oxa-aliphatic, 2-oxa-cycloaliphatic, 2-thialiphatic, or2-thia-cycloaliphatic hydrocarbon radical, a silyl or stannyl groupsubstituted by lower alkyl, halogeno lower alkyl, cycloalkyl, phenyl,phenyl-lower alkyl, lower alkoxy or halogen, or an alpha-phenyl-loweralkyl group having one or two phenyl groups, wherein phenyl may besubstituted by halogen or lower alkoxy, or in a 1-oxide thereof or ametal or an ammonium salt of such a compound having a sulpho or acarboxy group or an acid addition salt of such a compound having a basicamino group, the group R₃ ^(o) is split off and replaced by hydrogen bytreatment with hydrogen in the presence of a catalyst, with water, analcohol, or an organic or inorganic acid.
 2. Process according to claim1, characterised in that R₁ ^(a) represents an acyl group of the formula(A₂) or (A₃) and R₁ ^(b) represents hydrogen.
 3. Process according toclaim 1, characterised in that R₁ ^(a) represents phenylacetyl,phenyloxyacetyl or D-α-tert.-butyloxycarbonylamino-α-phenylacetyl and R₁^(b) represents hydrogen.
 4. Process according to claim 1, characterisedin that R₂ ^(A) represents benzyloxy, p-nitrobenzyloxy, diphenylmethoxy,lower alkoxy, 2-halogeno-lower alkoxy, or halogen.
 5. Process accordingto claim 1, characterised in that R₃ ^(o) is 1-lower alkoxy-1-loweralkyl, 1-lower alkylthio-1-lower alkyl, 2-oxa-lower alkylene,2-oxa-lower alkenylene, 2-thia-lower alkylene, or 2-thia-loweralkenylene.
 6. Process according to claim 1, characterised in that R₃^(o) is trimethylsilyl.
 7. Process according to claim 1, characterisedin that R₃ ^(o) is benzyl or diphenylmethyl.
 8. Process according toclaim 1 characterized in that R₃ ^(O) is split off by treatment withhydrogen in the presence of a catalyst, with water, an alcohol,hydrochloric acid, sulphuric acid, formic acid or trifluoroacetic acid.9. Process according to claim 1, characterised in that7β-phenoxyacetamido-3-hydroxy-3-cephem-4-carboxylic aciddiphenylmethylester is prepared from the corresponding3-trimethylsilyloxy compound by treatment with acetic acid.
 10. Processaccording to claim 1, characterised in that7β-phenoxyacetamido-3-hydroxy-3-cephem-4-carboxylic acidp-nitrobenzylester is prepared from the corresponding 3-benzyloxycompound by treatment with trifluoroacetic acid.